Heterocyclic antiviral compounds

ABSTRACT

This invention relates to piperidine derivatives of formulae Ia and Ib with substituents as defined herein useful in the treatment of a variety of disorders, including those in which the modulation of CCR5 receptors is implicated. More particularly, the present invention relates to 1-oxa-3,8-diaza-spiro[4.5]decan-2-one and 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one compounds and related derivatives, to compositions containing and to uses of such derivatives. Disorders that may be treated or prevented by the present derivatives include HIV and genetically related retroviral infections (and the resulting acquired immune deficiency syndrome, AIDS), diseases of the immune system and inflammatory diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Ser. No.60/543,408 filed Feb. 10, 2004, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

This invention relates to piperidine derivatives useful in the treatmentof a variety of disorders in which modulation of the CCR5 receptorligand binding is beneficial. More particularly, the present inventionrelates to 1-oxa-3,8-diaza-spiro[4.5]decan-2-one and1-oxa-3,9-diaza-spiro[5.5]undecan-2-one compounds and relatedderivatives, to compositions containing said compounds and to uses ofsuch derivatives. Disorders that may be treated or prevented by thepresent compounds include HIV and genetically related retroviralinfections (and the resulting acquired immune deficiency syndrome,AIDS), diseases of the immune system and inflammatory diseases.

BACKGROUND OF THE INVENTION

Compounds of the present invention modulate the activity of thechemokine CCR5 receptors. The chemokines are a large family ofpro-inflammatory peptides that exert their pharmacological effectthrough G-protein-coupled receptors. The name “chemokine”, is acontraction of “chemotactic cytokines”. The chemokines are a family ofleukocyte chemotactic proteins capable of attracting leukocytes tovarious tissues, which is an essential response to inflammation andinfection. Human chemokines include approximately 50 small proteins of50-120 amino acids that are structurally homologous. (M. Baggiolini etal., Ann. Rev. Immunol. 1997 15:675-705)

Modulators of the CCR5 receptor may be useful in the treatment ofvarious inflammatory diseases and conditions, and in the treatment ofinfection by HIV-1 and genetically related retroviruses. As leukocytechemotactic factors, chemokines play an indispensable role in theattraction of leukocytes to various tissues of the body, a process whichis essential for both inflammation and the body's response to infection.Because chemokines and their receptors are central to thepathophysiology of inflammatory and infectious diseases, agents whichmodulate CCR5 activity, preferably antagonizing interactions ofchemokines and their receptors, are useful in the therapeutic treatmentof such inflammatory and infectious diseases. The chemokine receptorCCR5 is of particular importance in the context of treating inflammatoryand infectious diseases. CCR5 is a receptor for chemokines, especiallyfor the macrophage inflammatory proteins (MIP) designated MIP-1a andMIP-1b, and for a protein which is regulated upon activation and isnormal T-cell expressed and secreted (RANTES).

HIV-1 infects cells of the monocyte-macrophage lineage and helper T-celllymphocytes by exploiting a high affinity interaction of the viralenveloped glycoprotein (Env) with the CD-4 antigen. The CD-4 antigen,however, appeared to be a necessary, but not sufficient requirement forcell entry and at least one other surface protein was required to infectthe cells (E. A. Berger et al., Ann. Rev. Immunol. 1999 17:657-700). Twochemokine receptors, either the CCR5 or the CXCR4 receptor weresubsequently found to be co-receptors along with CD4 which are requiredfor infection of cells by the human immunodeficiency virus (HIV). Thecentral role of CCR5 in the pathogenesis of HIV was inferred byepidemiological identification of powerful disease modifying effects ofthe naturally occurring null allele CCR5 Δ32. The Δ32 mutation has a32-basepair deletion in the CCR5 gene resulting in a truncated proteindesignated Δ32. Relative to the general population, Δ32/Δ32 homozygotesare significantly common in exposed/uninfected individuals suggestingthe role of CCR5 in HIV cell entry (R. Liu et al., Cell 199686(3):367-377; M. Samson et al., Nature 1996 382(6593):722-725). The CD4binding site on the gp120 of HIV appears to interact with the CD4molecule on the cell surface, and undergoes conformational changes whichallow it to bind to another cell-surface receptor, such as CCR5 and/orCXCR-4. This brings the viral envelope closer to the cell surface andallows interaction between gp41 on the viral envelope and a fusiondomain on the cell surface, fusion with the cell membrane, and entry ofthe viral core into the cell. Accordingly, an agent which could blockchemokine receptors in humans who possess normal chemokine receptorsshould prevent infection in healthy individuals and slow or halt viralprogression in infected patients.

RANTES, a natural ligand for the CCR5 receptor, and an analog chemicallymodified on the N-terminus, aminooxypentane RANTES, were found to blockHIV entry into the cells. (G. Simmons et al., Science 1997 276:276-279).Other compounds have been demonstrated to inhibit the replication ofHIV, including soluble CD4 protein and synthetic derivatives (Smith, etal., Science 1987 238:1704-1707), dextran sulfate, the dyes DirectYellow 50, Evans Blue, and certain azo dyes (U.S. Pat. No. 5,468,469).Some of these antiviral agents have been shown to act by blocking thebinding of gp120, the coat protein of HIV, to its target, the CD4glycoprotein of the cell.

A-M. Vandamme et al. (Antiviral Chemistry & Chemotherapy, 19989:187-203) disclose current HAART clinical treatments of HIV-1infections in man including at least triple drug combinations. Highlyactive anti-retroviral therapy (HAART) has traditionally consisted ofcombination therapy with nucleoside reverse transcriptase inhibitors(NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) andprotease inhibitors (PI). These compounds inhibit biochemical processesrequired for viral replication. In compliant drug-naive patients, HAARTis effective in reducing mortality and progression of HIV-1 to AIDS.While HAART has dramatically altered the prognosis for HIV infectedpersons, there remain many drawbacks to the current therapy includinghighly complex dosing regimes and side effects which can be very severe(A. Carr and D. A. Cooper, Lancet 2000 356(9239):1423-1430). Moreover,these multidrug therapies do not eliminate HIV-1 and long-term treatmentusually results in multidrug resistance, thus limiting their utility inlong term therapy. Development of new drug therapies to provide betterHIV-1 treatment remains a priority. Investigation of different classesof modulators of chemokine receptor activity, especially that of theCCR5 chemokine receptor, suggest inhibition of CCR5 as a new treatmentmodality.

Typical suitable NRTIs include zidovudine (AZT) available as RETROVIR®from Glaxo-Wellcome Inc.; didanosine (dd1) available as VIDEX® fromBristol-Myers Squibb Co.; zalcitabine (ddC) available as HIVID® fromRoche Pharmaceuticals; stavudine (d4T) available as ZERIT® fromBristol-Myers Squibb Co.; lamivudine (3TC) available as EPIVR® fromGlaxo-Wellcome; abacavir (1592U89) disclosed in WO96/30025 and availableZIAGEN® from Glaxo-Wellcome; adefovir dipivoxil [bis(POM)-PMEA]available as PREVON® from Gilead Sciences; lobucavir (BMS-180194), anucleoside reverse transcriptase inhibitor disclosed in EP-0358154 andEP-0736533 and under development by Bristol-Myers Squibb; BCH-10652, areverse transcriptase inhibitor (in the form of a racemic mixture ofBCH-10618 and BCH-10619) under development by Biochem Pharma;emitricitabine [(−)-FTC] licensed from Emory University under U.S. Pat.No. 5,814,639 and under development by Triangle Pharmaceuticals;beta-L-FD4 (also called beta-L-D4C and namedbeta-L-2′,3′-dicleoxy-5-fluoro-cytidene) licensed by Yale University toVion Pharmaceuticals; DAPD, the purine nucleoside,(−)-b-D-2,6-diamino-purine dioxolane disclosed in EP-0656778 andlicensed by Emory University and the University of Georgia to TrianglePharmaceuticals; and lodenosine (FddA),9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine, an acid stablepurine-based reverse transcriptase inhibitor discovered by the NIH andunder development by U.S. Bioscience Inc.

Typical suitable NNRTIs include nevirapine (BI-RG-587) available asVIRAMUNE® from Roxane Laboratories; delaviradine (BHAP, U-90152)available as RESCRIPTOR® from Pfizer; efavirenz (DMP-266) abenzoxazin-2-one disclosed in WO94/03440 and available as SUSTIVA® fromBristol-Myers Squibb Co.; PNU-142721, a furopyridine-thio-pyrimidineunder development by Pfizer 08807; AG-1549 (formerly Shionogi # S-1153);5-(3,5-dichlorophenyl)-thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethylcarbonate disclosed in WO 96/10019 and under development by AgouronPharmaceuticals, Inc.; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione)discovered by Mitsubishi Chemical Co. and under development by TrianglePharmaceuticals; and (+)-calanolide A (NSC-675451) and B, coumarinderivatives disclosed in NIH U.S. Pat. No. 5,489,697, licensed to MedChem Research, which is co-developing (+) calanolide A with Vita-investas an orally administrable product.

Typical suitable PIs include saquinavir (Ro 31-8959) available in hardgel capsules as IVIRASE® and as soft gel capsules as FORTOVASE® fromRoche Pharmaceuticals, Nutley, N.J. 07110-1199; ritonavir (ABT-538)available as NORVIR® from Abbott Laboratories; indinavir (MK-639)available as CRIXIVAN® from Merck & Co., Inc.; nelfiavir (AG-1343)available VIRACEPT® from Agouron Pharmaceuticals, Inc.; amprenavir(141W94), AGENERASE®, a non-peptide protease inhibitor under developmentby Vertex Pharmaceuticals, Inc. and available from Glaxo-Wellcome, underan expanded access program; lasinavir (BMS-234475) available fromBristol-Myers Squibb; DMP-450, a cyclic urea discovered by Dupont andunder development by Triangle Pharmaceuticals; BMS-2322623, anazapeptide under development by Bristol-Myers Squibb as a 2nd-generationHIV-1 PI; ABT-378 under development by Abbott; and AG-1549 an orallyactive imidazole carbamate discovered by Shionogi and under developmentby Agouron Pharmaceuticals, Inc.

Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside. Hydroxyurea (Droxia), a ribonucleoside triphosphatereductase inhibitor, the enzyme involved in the activation of T-cells,was discovered at the NCI and is in preclinical studies, it was shown tohave a synergistic effect on the activity of didanosine and has beenstudied with stavudine. IL-2 is disclosed in Ajinomoto EP-0142268,Takeda EP-0176299, and Chiron U.S. Pat. Nos. RE 33,653, 4,530,787,4,569,790, 4,604,377, 4,748,234, 4,752,585, and 4,949,314, and isavailable under the PROLEUKIN® (aldesleukin) as a lyophilized powder forIV infusion or sc administration upon reconstitution and dilution withwater; a dose of about 1 to about 20 million 1 U/day, sc is preferred; adose of about 15 million 1 U/day, sc is more preferred. IL-12 isdisclosed in WO96/25171 and is administered in a dose of about 0.5microgram/kg/day to about 10 microgram/kg/day, sc is preferred.Pentafuside (FUZEON®) a 36-amino acid synthetic peptide, disclosed inU.S. Pat. No. 5,464,933 that acts by inhibiting fusion of HIV-1 totarget membranes. Pentafuside (3-100 mg/day) is given as a continuous scinfusion or injection together with efavirenz and 2 PI's to HIV-1positive patients refractory to a triple combination therapy; use of 100mg/day is preferred. Ribavirin,1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is availablefrom ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; its manufacture andformulation are described in U.S. Pat. No. 4,211,771.

In addition to the potential for CCR5 modulators in the management ofHIV infections, the CCR5 receptor is an important regulator of immunefunction and compounds of the present invention may prove valuable inthe treatment of disorders of the immune system. Treatment of solidorgan transplant rejection, graft v. host disease, arthritis, rheumatoidarthritis, inflammatory bowel disease, atopic dermatitis, psoriasis,asthma, allergies or multiple sclerosis by administering to a human inneed of such treatment an effective amount of a CCR5 antagonist compoundof the present invention is also possible.

The pharmacokinetic challenges associated with large molecules, proteinsand peptides resulted in the establishment of programs to identify lowmolecular weight antagonists of CCR5. The efforts to identify chemokinemodulators have been reviewed (W. Kazmierski et al. Biorg Med. Chem.2003 11:2663-76; L. Agrawal and G. Alkhatib, Expert Opin. Ther. Targets2001 5(3):303-326; Chemokine CCR5 antagonists incorporating4-aminopiperidine scaffold, Expert Opin. Ther. Patents 200313(9):1469-1473; M. A. Cascieri and M. S. Springer, Curr. Opin. Chem.Biol. 2000 4:420-426, and references cited therein)

Takeda's program was the first to lead to fruition with theidentification of TAK-779 (M. Shiraishi et al., J. Med. Chem. 200043(10):2049-2063). Schering has advanced Sch-351125 into Phase I/IIclinical studies and reported the advance of a more potent follow upcompound, Sch417690 into Phase I studies. (S. W. McCrombie et al.,WO00066559; B. M. Baroudy et al. WO00066558; A. Palani et al., J Med.Chem. 2001 44(21):3339-3342; J. R. Tagat et al., J. Med. Chem. 200144(21):3343-3346; J. A. Esté, Cur. Opin. Invest. Drugs 20023(3):379-383).

Merck has disclosed the preparation of(2S)-2-(3-chlorophenyl)-1-N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzothiophene-3,4′-piperidin-1′-yl)butaneS-oxide (1) and related derivatives, trisubstituted pyrrolidines 2 andsubstituted piperidines 3 with good affinity for the CCR5 receptor andpotent-HIV activity. (P. E. Finke et al., Bioorg. Med. Chem. Lett., 200111:265-270; P. E. Finke et al., Bioorg. Med. Chem. Lett., 200111:2469-2475; P. E. Finke et al., Bioorg. Med. Chem. Lett., 200111:2475-2479; J. J. Hale et al., Bioorg. Med. Chem. Lett., 200111:2741-22745; D. Kim et al., Bioorg. Med. Chem. Lett., 200111:3099-3102)

WO0039125 (D. R. Armour et al.) and WO0190106 (M. Perros et al.)disclose heterocyclic compounds that are potent and selective CCR5antagonists. UK-427857 has advanced to clinical trials and show activityagainst HIV-1 isolates and laboratory strains (M. J. Macartney et al.,43^(rd) Intersci. Conf. Antimicrob. Agents Chemother. Sep. 14-17, 2003,Abstract H-875).

EP1236726 (H. Habashita et al.) discloses triazaspiro[5.5]undecanederivatives exemplified by AK602 which modulate the cytokine receptors.The compounds fall outside the scope of the current invention. (H.Nakata et al. Poster 546a, 11^(th) Conference on Retroviruses andOpportunistic Infections, San Francisco, Calif., Feb. 8-11, 2004; otheranalogs have also been disclosed, see, e.g. K. Maeda et al., J. Biol.Chem. 2001 276(37): 35194-35200)

WO03/057698 (N. Schlienger) describe1-oxa-3,8-diaza-spiro[4.5]decan-2-one compounds. More specificallyidentified are 3,4-di(optionallysubstituted)benzyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one compounds 4where R is alkyl optionally substituted by a cycloalkyl, heterocyclic,heteroaryl or aryl ring. The compounds of the invention modulatemonoamine receptors with selectively for the 5HT2A receptor. Thereference further teaches, but does not exemplify bicyclic compoundswherein R² and R³ together are an alkylene chain. These1-oxa-3,8-diaza-spiro[4.5]decan-2-ones compounds and methods do not fallwithin the scope of the present invention.1-Oxa-3,8-diazaspiro[4.5]decan-2-ones 5, and1,3,8-triazaspiro[4.5]decan-2-ones have been disclosed that aretachykinin NK_(a) receptor antagonists (P. W. Smith et al., J. Med.Chem. 1995 38(19):3772-79). Other 1-oxa-3,8-diaza-spiro[4.5]decan-2-onescompounds have been disclosed with α-adrenergic blocking activity (J. M.Caroon et al., J. Med. Chem. 1981 24(11):1320; R. M. Clark et al., J.Med. Chem. 1983 26(6):855-861). U.S. Pat. No. 3,399,192 (G. Regnier etal.) discloses 1-oxa-3,8-diaza-spiro[4.5]decan-2-ones compounds withanalgesic, anti-inflammatory CNS depressant and bronchodilator activity.EP414422 (E. Toth et al.) discloses1-oxa-3,8-diaza-spiro[4.5]decan-2-one compounds useful as antiallergicand psychotropic agents.

JP 63208590 (Yamanouchi Pharmaceuticals KK) disclose1-oxa-3,8-diaza-spiro[4.5]decane-2,4-dione compounds 6 useful fortreating CNS disorders. WO 2002102313 (J. Guo discloses pyrimidinecompounds containing the 1-oxa-3,8-diaza-spiro[4.5]decane-2,4-dioneradical useful for inhibiting phosphodiesterase. These compounds falloutside the scope of the present invention.

1,3,8-Triaza-spiro[4.5]decan-4-one compounds 7 have be disclosed blockbinding at the bradykinin B2 receptor and antagonize bradykinin mediatedactions in vivo (B. J. Mavunkel et al. J. Med. Chem. 199639(16):3169-73). Other related 1-oxa-3,8-diaza-spiro[4.5]decan-2-oneshave been disclosed: GB 1478932 (G. Regnier et al.) as anti-anaphylacticand bronchodilating compounds; J. Maillard, Eur. J. Med. Chem. 19749(2):128-132 as adrenolytic compounds; J. Maillard, Chim. Ther. 19727(6):458-466; J. Maillard, J. Med. Chem. 1972 15(11):1123-1128 asanalgetic and adrenolytic compounds; U.S. Pat. No. 3,721,675 (J.Maillard). 1-oxa-3,9-diazaspiro[5.5]undecan-2-ones also were disclosedto have neuroleptic activity (J. Maillard, Eur. J. Med. Chem. 19749(4):416-423). WO200130780 (R. M. Scarborough et al.) and WO9711940 (J.M. Fisher) disclose compounds which generically encompass the1-oxa-3,8-diaza-spiro[4.5]decan-2-one ring system as inhibitors ofthrombosis and platelet aggregation. WO9965494 (M. W. Embry et al.)disclose oxadiaza- and triazaspiro[4.5]decylmethylimidazoles and analogsas inhibitors of prenyl-protein transferase.

WO200292604 (H. Cai et al.) disclose compounds related to9-benzoyl-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-ones 8 which areuseful for the treatment of diseases associated with the neurokinin 1receptor. WO9711940 (M. J. Fisher et al.) disclose1-oxa-3,9-diaza-spiro[5.5]undecan-2-one compounds as inhibitors offibrinogen-mediated platelet aggregation. WO200157044 (H. Horino et al.)discloses fused 1-oxa-3,9-diazaispiro[5.5]undecan-2-ones which aremonocyte chemotactic protein-1 (MCP-1 antagonists)4-Substituted-1-oxa-3,9-diazaispiro[5.5]undecan-2-ones compounds havebeen disclosed which are claimed to have neuroleptic properties (J.Bassus et al. Eur. J. Med. Chem. 1974 9(4):416-423) These compounds falloutside the scope of the present invention.

SUMMARY OF THE INVENTION

The present invention relates to a compounds according to formulae Ia orIb, methods for treating diseases alleviated by administration of acompound according to formulae Ia or Ib that is a CCR5 antagonists andpharmaceutical compositions for treating diseases containing a compoundaccording to formulae Ia or Ib admixed with at least one carrier,diluent or excipient,

wherein:

-   A is (CH₂)_(q);-   R¹ is C(═O)R⁴, C(═O)X, or S(O)_(p);-   X is NR⁵R⁶ or OR¹¹;-   R^(2a) and R^(2b) are (A), independently    -   (i) hydrogen,    -   (ii) C₁₋₁₀ alkyl,    -   (iii) C₂₋₁₀ alkenyl    -   (iv) C₁₋₁₀ haloalkyl,    -   (v) C₃₋₇ cycloalkyl,    -   (vi) C₃₋₇ cycloalkyl-C₁₋₃ alkyl,    -   (vii) C₁₋₁₀ heteroalkyl,    -   (viii) C₁₋₁₀ alkylidene,

(ix) C₁₋₁₀ heteroalkylidene,

-   -   (x) aryl,    -   (xi) aryl-C₁₋₃ alkyl,    -   (xii) heteroaryl,    -   (xiii) heteroaryl-C₁₋₃ alkyl,    -   (xiv) C₁₋₁₀ alkyl wherein 2 or 3 nonadjacent carbon atoms are        independently replaced with —O—, —S(O)_(p)—, —NH— or NR,    -   (xv) —(CH₂)_(w)R⁸ wherein w is an integer form 2 to 6, and the        C₂-C₆ alkylene chain optionally contains a double bond;    -   (xvi) —(CH₂)_(w)CH═NR⁹ wherein w is an integer from 2 to 6; or    -   (B), together with the carbon atoms to which they are attached,        are o-phenylene optionally substituted with 1 to 3 substituents        independently selected from the group consisting of C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ thioalkyl, C₁₋₆ alkylsulfonyl,        hydroxyl, halogen, NR^(5a)R^(6a), cyano and nitro with the        proviso that if R^(2a), R^(2b), together with the carbon atoms        to which they are optionally substituted o-phenylene, m is 1;

-   R³ is (i) C₁₋₁₀ alkyl,    -   (ii) C₂₋₁₀ alkenyl    -   (iii) C₁₋₁₀ heteroalkyl,    -   (iv) C₃₋₇ cycloalkyl,    -   (v) C₁₋₆ alkyl-C₃₋₇ cycloalkyl,    -   (vi) heterocycle C₁₋₆ alkyl,    -   (vii) aryl,    -   (viii) aryl-C₁₋₃ alkyl,    -   (ix) heteroaryl,    -   (x) heteroaryl C₁₋₆ alkyl,    -   (xi) C(═O)R^(3a) wherein R^(3a) is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or        C₃₋₇ cycloalkyl, or    -   (xii) a fragment of formula IIa-IIc;

-   R⁴ is (i) C₁₋₁₀ alkyl,    -   (ii) C₃₋₇ cycloalkyl-C₁₋₁₀ substituted alkyl,    -   (iii) heterocycle,    -   (iv) aryl, or    -   (v) heteroaryl;-   R⁵ and R⁶ are (A) when taken independently are hydrogen, C₁₋₁₀    alkyl, C₁₋₁₀ heteroalkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyl-C₃₋₇    cycloalkyl, heterocycle C₁₋₆ alkyl, aryl, aryl-C₁₋₃ alkyl,    heteroaryl or heteroaryl C₁₋₆ alkyl; or,    -   (B) C₃₋₆ alkylene or [(CH₂)₂]₂O when taken together;-   R^(5a) and R^(6a) are (A) hydrogen, C₁₋₆ alkyl or C₁₋₆ alkylcarbonyl    when taken independently, or,    -   (B) C₃₋₆ alkylene or [(CH₂)₂]₂O when taken together;-   R⁷ is hydrogen, cyano or C₁₋₆ alky;-   R⁸ is —CN, —NO₂, —CONR^(5a)R^(6a), COR⁹, —NHSO₂C₁₋₆ alkyl;-   R⁹ is OH or C₁₋₆ alkoxy;-   R¹⁰ is N or N⁺—O⁻;-   R¹¹ is C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₃₋₇ cycloalkyl, C₁₋₆    alkyl-C₃₋₇ cycloalkyl, heterocycle C₁₋₆ alkyl, aryl, aryl-C₁₋₃    alkyl, heteroaryl or heteroaryl C₁₋₆ alkyl;-   m is 0 or 1;-   n is independently 0 to 2;-   o is independently 0 or 1;-   p is 0 to 2;-   q is 1 to 3;    wherein,    -   each said heteroaryl is independently selected from the group        consisting of pyridyl, 1-oxy-pyridinyl, pyrimidyl, oxypyrimdyl,        pyrazinyl, pyridazinyl, pyrrolyl, thienyl, furyl, imidazolyl,        pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl        indolinyl, N-Boc-indolinyl, quinolinyl, isoquinolinyl,        benzofuranyl, 4,5,6,7-tetrahydrobenzofuranyl and        1,2,3,4-tetrahydroacridinyl;    -   each said aryl and said heteroaryl are optionally independently        substituted with 1 to 3 substituents selected from the group        consisting of hydroxy, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₁₋₆ thioalkyl, aryl, aryl C₁₋₃ alkyl, aryloxy,        heteroaryloxy, thioaryl, thioheteroaryl, aryl C₁₋₃ alkoxy,        heteroaryl, heterocyclyl, heterocycle C₁₋₆ alkyl, C₁₋₆        alkylsulfonyl, —NIHSO₂C₁₋₆ alkyl, SO₂NR^(5a)R^(6a),        (CH₂)_(u)CO₂R⁹, (CH₂)_(u)CONR^(5a)R^(6a), —X¹C(═O)X², C₁₋₁₀        alkylcarbonyl, halogen, NR^(5a)R^(6a), cyano, nitro and C₁₋₁₀        alkyl wherein 2 or 3 nonadjacent carbon atoms are independently        replaced with —O—, —S(O)_(p)—, —NH— or NR⁵, wherein u is an        integer from 0 to 6, X¹ is NR^(5b) or O; X² is NR⁵R⁶ or OR³ and        R^(5b) is H or C₁₋₆ alkyl;    -   each said heterocycle is independently selected from the group        consisting of pyrrolidinyl, 1-methyl-pyrrolidinyl, piperidinyl,        morpholinyl, thiomorpholinyl, tetrahydrofuranyl, dioxolanyl and        pyranyl optionally substituted with 1 to 3 substituents        independently selected from the group consisting of hydroxy C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ thioalkyl, C₁₋₆        alkylsulfonyl, halogen, NR^(5a)R^(6a), cyano and nitro;        pure enantiomers, partially resolved enantiomers, racemic        mixtures, pharmaceutically acceptable acid addition salts,        hydrates and solvates thereof.

Compounds and compositions of the present invention are useful fortreating diseases mediated by human immunodeficiency virus in humans.Compounds and compositions of the present invention also may be used fortreatment of respiratory disorders, including adult respiratory distresssyndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructivepulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis andchronic sinusitis. Conditions triggered, affected or are in any otherway correlated with T-cell trafficking in different organs may betreated with compounds of the invention. Compounds of the presentinvention may be useful for the treatment of such conditions and inparticular, but not limited to the following for which a correlationwith CCR5 or CCR5 chemokines has been established: inflammatory boweldisease, including Crohn's disease and ulcerative colitis, multiplesclerosis, rheumatoid arthritis, graft rejection, in particular but notlimited to kidney and lung allografts, endometriosis, type I diabetes,renal diseases, chronic pancreatitis, inflammatory lung conditions orchronic heart failure. For recent reviews of possible applications ofchemokines and chemokine receptor blockers see: Cascieri, M. A., andSpringer, M. S., The chemokine/chemokine receptor family: potential andprogress for therapeutic intervention, Curr. Opin. Chem. Biol. 20004(4):420-7; A. E. I. Proudfoot The Strategy of Blocking the ChemokineSystem to Combat Disease, Immunol. Rev. 2000 177:246-256.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention there is provided a compoundaccording to formulae Ia or Ib wherein A, X, X¹, X², R¹, R^(2a), R^(2b),R³, R⁴, R⁵, R^(5a), R⁶, R^(6a), R⁷, R¹, R⁹, R¹⁰, R¹¹, m, n, o, p, q, u,w, heteroaryl, substituted aryl, substituted heteroaryl and heterocycleare as defined hereinabove.

In another embodiment of the present invention there is provided acompound according to formulae Ia″ or Ib″ wherein A, X, R¹, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹¹, m, n, o, p and q are as defined hereinabove, andwherein:

-   -   R^(2a) and R^(2b) are (A), independently hydrogen, C₁₋₁₀ alkyl,        C₁₋₁₀ haloalkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkyl-C₃₋₇ cycloalkyl,        C₁₋₁₀ heteroalkyl, C₁₋₁₀ alkylidene, C₁₋₁₀ heteroalkylidene,        —(CH₂)_(q)R⁸, aryl, aryl-C₁₋₃ alkyl, heteroaryl, heteroaryl-C₁₋₃        alkyl, C₁₋₁₀ alkyl wherein 2 or 3 nonadjacent carbon atoms are        independently replaced with —O—, —S(O)_(p)—, —NH— or NR⁵, or        (B), together with the carbon atoms to which they are attached,        are o-phenylene optionally substituted with 1 to 3 substituents        independently selected from the group consisting of C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ thioalkyl, C₁₋₆ alkylsulfonyl,        halogen, NR^(5a)R^(6a), cyano and nitro with the proviso that if        R^(2a) and R^(2b), together with the carbon atoms to which they        are optionally substituted o-phenylene, m is 1;    -   R³ is C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₃₋₇ cycloalkyl, C₁₋₆        alkyl-C₃₋₇ cycloalkyl, heterocycle C₁₋₆ alkyl, aryl, aryl-C₁₋₃        alkyl, heteroaryl, heteroaryl C₁₋₆ alkyl;    -   R^(5a) and R^(6a) are (A) hydrogen, C₁₋₆ alkyl or C₁₋₆        alkylcarbonyl when taken independently or (B) C₃₋₆ alkylene when        together;    -   q is an integer from 1 to 3;    -   each said heteraryl is independently selected from the group        consisting of pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,        pyrrolyl. thienyl, furyl, imidazolyl, pyrazolyl, oxazolyl,        thiazolyl, isoxazolyl and isothiazolyl,    -   each said aryl and said heteroaryl are optionally independently        substituted with 1 to 3 substituents selected from the group        consisting of hydroxy, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        C₁₋₆ thioalkyl, C₁₋₆ alkylsulfonyl, halogen, NR^(5a)R^(6a),        cyano and nitro;    -   each said heterocycle is independently selected from the group        consisting of pyrrolidinyl, 1-methyl-pyrrolidinyl; piperidinyl,        tetrahydrofuranyl, and pyranyl optionally substituted with 1 to        3 substituents independently selected from the group consisting        of hydroxy C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆        thioalkyl, C₁₋₆ alkylsulfonyl, halogen, NR^(5a)R^(6a), cyano and        nitro.

In another embodiment of the present invention there is provided acompound according to formula Ic wherein R^(2a) is C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₃ alkyl, C₁₋₁₀heteroalkyl, C₁₋₁₀ alkylidene, C₁₋₁₀ heteroalkylidene or C₁₋₁₀ alkylwherein 2 or 3 nonadjacent carbon atoms are independently replaced with—O—, —S(O)_(p)—, —NH— or NR⁵; R^(2b) is hydrogen; R³ is C₁₋₁₀ alkyl,C₃₋₇ cycloalkyl, C₁₋₆ alkyl-C₃₋₇ cycloalkyl, optionally substitutedaryl, optionally substituted aryl-C₁₋₃ alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl-C₁₋₆ alkyl; R⁴ is C₁₋₁₀alkyl, optionally substituted aryl or optionally substituted heteroaryl;R⁷ is hydrogen or C₁₋₆ alkyl; n and o are 1; p is 2; and X, X¹, X², R¹,R⁵, R^(5a), R⁶, R^(6a), R⁹, R¹⁰, R¹¹, m, u, heteroaryl, substitutedaryl, substituted heteroaryl and heterocycle are as defined hereinabove.

In another embodiment of the present invention there is provided acompound according to formula Ic wherein R^(2a) is C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₃ alkyl, C₁₋₁₀heteroalkyl, C₁₋₁₀ alkylidene, C₁₋₁₀ heteroalkylidene or C₁₋₁₀ alkylwherein 2 or 3 nonadjacent carbon atoms are independently replaced with—O—, —S(O)_(p)—, —NH— or NR⁵; R^(2b) is hydrogen; R³ is C₁₋₁₀ alkyl,C₃₋₇ cycloalkyl, C₁₋₆ alkyl-C₃₋₇ cycloalkyl, optionally substitutedaryl, optionally substituted aryl-C₁₋₃ alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl-C₁₋₆ alkyl; R⁴ is C₁₋₁₀alkyl, optionally substituted aryl or optionally substituted heteroaryl;R⁷ is hydrogen or methyl; p is 2; and X, X¹, X², R¹, R⁵, R^(5a), R⁶,R^(6a), R⁹, R¹⁰, R¹¹, m, u, heteroaryl, substituted aryl, substitutedheteroaryl and heterocycle are as defined hereinabove.

In another embodiment of the present invention there is provided acompound according to formula Ic wherein R¹ is COR⁴; R^(2a) is C₁₋₁₀alkyl, C₁₋₁₀ heteroalkyl or C₁₋₁₀ alkyl wherein 2 or 3 nonadjacentcarbon atoms in the alkyl chain optionally can be independently replacedwith —O—, —S(O)_(p)—, —NH— or NR⁵; R^(2b) is hydrogen; R³ is C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyl-C₃₋₇ cycloalkyl, optionallysubstituted aryl, optionally substituted aryl-C₁₋₃ alkyl, optionallysubstituted heteroaryl, optionally substituted heteroaryl-C₁₋₆ alkyl; R⁴is optionally substituted aryl or optionally substituted heteroaryl; R⁷is hydrogen or methyl; R¹⁰ is N; p is 2; and, X¹, X, R⁵, R^(5a), R⁶,R^(6a), R⁹, m, u, heteroaryl, substituted aryl, substituted heteroaryland heterocycle are as defined hereinabove.

In another embodiment of the present invention there is provided acompound according to formula Ic wherein R¹ is COR⁴; R^(2a) is C₁₋₁₀alkyl, C₁₋₁₀ heteroalkyl or C₁₋₁₀ alkyl wherein 2 or 3 nonadjacentcarbon atoms in the alkyl chain optionally can be independently replacedwith —O—, —S(O)_(p)—, —NH— or NR⁵; R^(2b) is hydrogen; R³ is C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyl-C₃₋₇ cycloalkyl, optionallysubstituted aryl, optionally substituted aryl-C₁₋₃ alkyl, optionallysubstituted heteroaryl, optionally substituted heteroaryl-C₁₋₆ alkyl; R⁴is optionally substituted aryl; R⁷ is hydrogen or methyl; R¹⁰ is N; p is2; and X¹, X², R⁵, R^(5a), R⁶R^(6a), R⁹, m, u, heteroaryl, substitutedaryl, substituted heteroaryl and heterocycle are as defined hereinabove.

In another embodiment of the present invention there is provided acompound according to formula Ic wherein R¹ is COR⁴; R^(2a) is C₁₋₁₀alkyl, C₁₋₁₀ heteroalkyl or C₁₋₁₀ alkyl wherein 2 or 3 nonadjacentcarbon atoms in the alkyl chain optionally can be independently replacedwith —O—, —S(O)_(p)—, —NH— or NR⁵; R^(2b) is hydrogen; R³ is C₁₋₁₀allyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyl-C₃₋₇ cycloalkyl, optionallysubstituted aryl, optionally substituted aryl-C₁₋₃ alkyl, optionallysubstituted heteroaryl, optionally substituted heteroaryl-C₁₋₆ alkyl; R⁴is optionally substituted phenyl, 1-naphthyl or 2-naphthyl; R⁷ ishydrogen or methyl; R¹⁰ is N; p is 2; and X¹, X², R⁵, R^(5a), R⁶,R^(6a), R⁹, m, u, heteroaryl, substituted aryl, substituted heteroaryland heterocycle are as defined hereinabove.

In another embodiment of the present invention there is provided acompound according to formula Ic wherein R¹ is COR⁴; R^(2a) is C₁₋₁₀alkyl, C₁₋₁₀ heteroalkyl or C₁₋₁₀ alkyl wherein 2 or 3 nonadjacentcarbon atoms in the alkyl chain optionally can be independently replacedwith —O—, —S(O)_(p)—, —NH— or NR⁵; R^(2b) is hydrogen; R³ is C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyl-C₃₋₇ cycloalkyl, optionallysubstituted aryl, optionally substituted aryl-C₁₋₃ alkyl, optionallysubstituted heteroaryl, optionally substituted heteroaryl-C₁₋₆ alkyl; R⁴is optionally substituted heteroaryl; R⁷ is hydrogen or methyl; R¹⁰ isN; p is 2; X¹, X², R⁵, R^(5a), R⁶, R^(6a), R⁹, m, u, heteroaryl,substituted aryl, substituted heteroaryl and heterocycle are as definedhereinabove.

In another embodiment of the present invention there is provided acompound according to formula Ic wherein R¹ is COR⁴; R^(2a) is C₁₋₁₀alkyl, C₁₋₁₀ heteroalkyl or C₁₋₁₀ alkyl wherein 2 or 3 nonadjacentcarbon atoms in the alkyl chain optionally can be independently replacedwith —O—, —S(O)_(p)—, —NH— or NR⁵; R^(2b) is hydrogen; R³ is C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyl-C₃₋₇ cycloalkyl, optionallysubstituted aryl, optionally substituted aryl-C₁₋₃ alkyl, optionallysubstituted heteroaryl, heteroaryl-C₁₋₆ alkyl; R⁴ is optionallysubstituted pyridyl, optionally substituted pyrimidyl, optionallysubstituted pyrazolyl, optionally substituted oxazolyl, optionallysubstituted isoxazolyl or optionally substituted pyrrolyl; R⁷ ishydrogen or methyl; R¹⁰ is N; p is 2; X¹, X², R⁵R^(5a), R⁶, R^(6a), R⁹,m, u, heteroaryl, substituted aryl, substituted heteroaryl andheterocycle are as defined hereinabove.

In another embodiment of the present invention there is provided acompound according to formula 1d wherein R¹ is COR⁴; R^(2a) is C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₃ alkyl,C₁₋₁₀ heteroalkyl, C₁₋₁₀ alkylidene, C₁₋₁₀ heteroalkylidene or C₁₋₁₀alkyl wherein 2 or 3 nonadjacent carbon atoms are independently replacedwith —O—, —S(O)_(p)—, —NH— or NR⁵; R^(2b) is hydrogen; R³ is either asdefined in claim 1 or in claim 2; R⁴ is optionally substituted aryl oroptionally substituted heteroaryl; R⁷ is hydrogen or C₁₋₆ alkyl; n and oare 1; p is 2; A, X¹, X², R³, R⁵, R^(5a), R⁶, R^(6a), R⁹, R¹, m, q, u,heteroaryl, substituted aryl, substituted heteroaryl and heterocycle areas defined hereinabove.

In another embodiment of the present invention there is provided acompound according to formula Id wherein A is (CH₂)₂; R¹ is COR⁴; R^(2a)is C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₃alkyl, C₁₋₁₀ heteroalkyl, C₁₋₁₀ alkylidene, C₁₋₁₀ heteroalkylidene orC₁₋₁₀ alkyl wherein 2 or 3 nonadjacent carbon atoms are independentlyreplaced with —O—, —S(O)_(p)—, —NH— or NR⁵; R^(2b) is hydrogen; R³ iseither as defined in claim 1 or in claim 2; R⁴ is optionally substitutedaryl or optionally substituted heteroaryl; R⁷ is hydrogen or C₁₋₆ alkyl;n and o are 1; p is 2; X¹, X², R³, R⁵, R^(5a), R⁶, R^(6a), R⁹, R¹⁰, m,q, u, heteroaryl, substituted aryl, substituted heteroaryl andheterocycle are as defined hereinabove.

In another embodiment of the present invention there is provided acompound according to formula Ie wherein R^(2a) and R^(2b) areoptionally substituted o-phenylene; R³ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl,C₁₋₆ alkyl-C₃₋₇ cycloalkyl, optionally substituted aryl, optionallysubstituted aryl-C₁₋₃ alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-C₁₋₃ alkyl; R⁴ is optionallysubstituted aryl or optionally substituted heteroaryl; R⁷ is hydrogen orC₁₋₆ alkyl; R¹² in each occurrence is independently hydroxy, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ thioalkyl, C₁₋₆ alkylsulfonyl,halogen, NR^(5a)R^(6a), cyano and nitro; m is 1; n and o are 1; p is 2;and, R¹, R⁵, R^(5a), R⁶, R^(6a), R⁹, R¹⁰, u, heteroaryl, substitutedaryl, substituted heteroaryl and heterocycle are as defined hereinabove.

In another embodiment of the present invention there is provided acompound according to formulae Ia or Ib selected from:

-   5-Butyl-9-[1-(4,6-dimethyl-2-trifluoromethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;    compound with trifluoro-acetic acid-   5-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;    compound with trifluoro-acetic acid-   5-Butyl-3-(4,4-difluoro-cyclohexylmethyl)-9-[1-(4,6-dimethyl-2-trifluoromethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;    compound with trifluoro-acetic acid-   5-Butyl-3-(4,4-difluoro-cyclohexylmethyl)-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;    compound with trifluoro-acetic acid-   5-Butyl-9-{1-[1-(4-fluoro-phenyl)-3,5-dimethyl-1H-pyrazole-4-carbonyl]-4-methyl-piperidin-4-yl}-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;    compound with trifluoro-acetic acid-   5-Butyl-9-{1-[3-(4-methoxy-phenyl)-5-methyl-isoxazole-4-carbonyl]-4-methyl-piperidin-4-yl}-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;    compound with trifluoro-acetic acid-   (S)-5-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one-   (R)-5-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one-   5-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;    compound with trifluoro-acetic acid-   5-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;    compound with trifluoro-acetic acid-   5-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;    compound with trifluoro-acetic acid-   5-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;    compound with trifluoro-acetic acid-   5-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-piperidin-4-yl]-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;    compound with trifluoro-acetic acid

In another embodiment of the present invention there is provided amethod for treating or preventing an human immunodeficiency virus (HIV)infection, or treating AIDS or ARC, in a patient in need thereof whichcomprises administering to the patient a therapeutically effectiveamount of a compound according to formulae Ia or Ib wherein A, X, X¹,X², R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R^(5a), R⁶, R^(6a), R⁷, R⁸, R⁹, R¹⁰,R¹¹, m, n, o, p, q, u, w, heteroaryl, substituted aryl, substitutedheteroaryl and heterocycle are as defined hereinabove.

In another embodiment of the present invention there is provided amethod for treating a mammal having a disease mediated by humanimmunodeficiency virus comprising co-administering to a mammal, a CCR5receptor antagonist of formulae Ia or Ib wherein A, X, X¹, X², R¹,R^(2a), R^(2b), R³, R⁴, R⁵, R^(5a), R⁶, R^(6a), R⁷, R⁸, R⁹, R¹⁰, R¹¹, m,n, o, p, q, u, w, heteroaryl, substituted aryl, substituted heteroaryland heterocycle are as defined hereinabove and at least one compoundselected from the group consisting of HIV nucleoside reversetranscriptase, HIV nonnucleoside reverse transcriptase, HIV proteaseinhibitor and viral fusion inhibitors.

In another embodiment of the present invention there is provided amethod for treating a mammal having a disease mediated by humanimmunodeficiency virus comprising co-administering to a mammal, a CCR5receptor antagonist of formulae Ia or Ib wherein A, X, X¹, X², R¹,R^(2a), R^(2b), R³, R⁴, R⁵, R^(5a), R⁶, R^(6a)R⁷, R⁸, R⁹, R¹⁰, R¹¹, m,n, o, p, q, u, w, heteroaryl, substituted aryl, substituted heteroaryland heterocycle are as defined hereinabove and at least one reversetranscriptase inhibitor selected from the group consisting ofzidovudine, lamivudine, didanosine, zalcitabine, stavudine, rescriptor,sustiva and viramune, efavirenz, nevirapine or delavirdine, and/or thenucleoside reverse transcriptase inhibitor selected from the groupconsisting of zidovudine, didanosin, zalcitabine, stavudine, lamivudine,abacavir, adefovir and dipivoxil, and/or the protease inhibitor selectedfrom the group consisting of saquinavir, ritonavir, nelfinavir,indinavir, amprenavir, lopinavir.

In another embodiment of the present invention there is provided amethod for treating a mammal having a disease state that is alleviatedby treating the mammal with a CCR5 receptor antagonist wherein thedisease state is solid organ transplant rejection, graft v. hostdisease, arthritis, rheumatoid arthritis, inflammatory bowel disease,atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosiscomprising co-administering a compound of formulae Ia or Ib wherein A,X, X¹, X², R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R^(5a), R⁶, R^(6a), R⁷, R⁸,R⁹, R¹⁰, R¹¹, m, n, o, p, q, u, w, heteroaryl, substituted aryl,substituted heteroaryl and heterocycle are as defined hereinabove.

In another embodiment of the present invention there is provided amethod for treating a human having a disease state that is alleviated bytreating the human with a CCR5 receptor antagonist wherein the diseasestate is solid organ transplant rejection, graft v. host disease,arthritis, rheumatoid arthritis, inflammatory bowel disease, atopicdermatitis, psoriasis, asthma, allergies or multiple sclerosiscomprising co-administering a compound of formulae Ia or Ib wherein A,X, X¹, X², R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R^(5a), R⁶, R^(6a), R⁷, R⁸,R⁹, R¹⁰, R¹¹, m, n, o, p, q, u, w, heteroaryl, substituted aryl,substituted heteroaryl and heterocycle are as defined hereinabove, andat least one other immune modulator.

In another embodiment of the present invention there is provided apharmaceutical composition comprising a compound according to formulaeIa or Ib wherein A, X, X¹, X², R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R^(5a),R⁶, R^(6a), R⁷, R⁸, R⁹, R¹⁰, R¹¹, m, n, o, p, q, u, w, heteroaryl,substituted aryl, substituted heteroaryl and heterocycle are as definedhereinabove admixed with at least one pharmaceutical acceptable carrier,diluent or excipient.

DEFINITIONS

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “as defined hereinabove” refers to the first definitionprovided in the Summary of the Invention.

The term “optional” or “optionally” as used herein means that asubsequently described event or circumstance may, but need not, occur,and that the description includes instances where the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted” means that the moiety may be hydrogen or asubstituent.

It is contemplated that the definitions described herein may be appendedto form chemically-relevant combinations, such as “heteroalkylaryl,”“haloalkylheteroaryl,” “arylalkylheterocyclyl,” “alkylcarbonyl,”“alkoxyalkyl,” and the like.

The term “alkyl” as used herein denotes an unbranched or branched chain,saturated, monovalent hydrocarbon residue containing 1 to 10 carbonatoms. The term “lower alkyl” denotes a straight or branched chainhydrocarbon residue containing 1 to 6 carbon atoms. “C₁₋₁₀ alkyl” asused herein refers to an alkyl composed of 1 to 10 carbons. Examples ofalkyl groups include, but are not limited to, lower alkyl groups includemethyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl,isopentyl, neopentyl, hexyl, heptyl, and octyl.

When the term “alkyl” is used as a suffix following another term, as in“phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkylgroup, as defined above, being substituted with one to two substituents(preferably one substituent) selected from the other, specifically-namedgroup. Thus, for example, “phenylalkyl” refers to an alkyl group havingone to two phenyl substituents, and thus includes benzyl, phenylethyl,and biphenyl. An “alkylaminoalkyl” is an alkyl group having one to twoalkylamino substituents. “Hydroxyalkyl” includes 2-hydroxyethyl,2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl,2,3-dihydroxybutyl, 2-(hydroxymethyl)-3-hydroxypropyl, and so forth.Accordingly, as used herein, the term “hydroxyalkyl” is used to define asubset of heteroalkyl groups defined below.

The term “alkylidene” as used herein means a bivalent radical ═CRR′,wherein R and R′ are independently alkyl radicals or hydrogen wherealkyl is as defined herein. Examples of alkylidenyl radicals include,but are not limited to, ethylidene, butylidene, pentylidene and1-methyl-butylidene.

The term “alkenyl” or “alkene” as used herein denotes an unsubstitutedhydrocarbon chain radical having from 2 to 10 carbon atoms having one ortwo olefinic double bonds. C₂₋₁₀ alkenyl” as used herein refers to analkenyl composed of 2 to 10 carbons. Examples are vinyl, 1-propenyl,2-propenyl (allyl) or 2-butenyl (crotyl). Examples of the correspondingalkene are ethane, 1-propene, 2-propene and 2-butene.

The term “haloalkyl” as used herein denotes an unbranched or branchedchain alkyl group as defined above wherein 1, 2, 3 or more hydrogenatoms are substituted by a halogen. Examples are 1-fluoromethyl,1-chloromethyl, 1-bromomethyl, 1-iodomethyl, trifluoromethyl,trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl,1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl,2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3-bromopropyl or2,2,2-trifluoroethyl.

The term “cycloalkyl” as used herein denotes a saturated carbocyclicring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. “C₃₋₇ cycloalkyl” asused herein refers to a cycloalkyl composed of 3 to 7 carbons in thecarbocyclic ring.

The term “cycloalkyl alkyl” as used herein refers to the radical R′R″—,wherein R′ is a cycloalkyl radical as defined herein, and R″ is analkylene radical as defined herein with the understanding that theattachment point of the cycloalkylalkyl moiety will be on the alkyleneradical. Examples of cycloalkylalkyl radicals include, but are notlimited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl. C₃₋₇cycloalkyl-C₁₋₃ alkyl refers to the radical R′R″ where R′ is C₃₋₇cyclolalkyl and R″ is C₁₋₃ alkylene as defined herein.

The term “heteroalkyl” as used herein means an alkyl radical as definedherein wherein one, two or three hydrogen atoms have been replaced witha substituent independently selected from the group consisting of—OR^(a), —NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0to 2), with the understanding that the point of attachment of theheteroalkyl radical is through a carbon atom, wherein R^(a) is hydrogen,acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) areindependently of each other hydrogen, acyl, alkyl, cycloalkyl, orcycloalkylalkyl; and when n is 0, R^(d) is hydrogen, alkyl, cycloalkyl,or cycloalkylalkyl, and when n is 1 or 2, R^(d) is alkyl, cycloalkyl,cycloalkylalkyl, amino, acylamino, or alkylamino. Alternatively aheteroalkyl group is an alkyl radical wherein one or more of the carbonatoms is replaced by —O—, NR^(b)—, or —S(O)_(n)—. Representativeexamples include, but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

The term “alkylene” as used herein denotes a divalent saturated linearhydrocarbon radical of 1 to 10 carbon atoms or a branched saturateddivalent hydrocarbon radical of 3 to 10 carbon atoms, unless otherwiseindicated. Examples of alkylene radicals include, but are not limitedto, methylene, ethylene, propylene, 2-methyl-propylene, butylene and2-ethylbutylene.

The term “heteroalkylidenyl” or “heteroalkylidene” as used herein meansa bivalent radical ═CRR′, wherein R is an heteroalkyl radical, anhaloalkyl radical, an alkyl radical, or hydrogen, and R′ is anheteroalkyl radical or an haloalkyl radical, as defined herein. Examplesof heteroalkylidenyl radicals include, but are not limited to,3,3,3-trifluoropropylidenyl, 2-hydroxybutylidenyl, 3-aminopropylidenyl,and the like.

The term “aryl” as used herein denotes a monovalent aromatic carbocyclicradical containing 5 to 15 carbon atoms consisting of one individualring, or one or more fused rings in which at least one ring is aromaticin nature, which can optionally be substituted with one or more,preferably one or three substituents independently selected fromhydroxy, thio, cyano, alkyl, alkoxy, lower haloalkoxy, alkylthio,halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino,alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl, alkylsulfonyl, arylsulfinyl, alkylaminosulfonyl,arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, carbamoyl,alkylcarbamoyl and dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino,arylcarbonylamino, unless otherwise indicated. Alternatively twoadjacent atoms of the aryl ring may be substituted with a methylenedioxyor ethylenedioxy group. Examples of aryl radicals include, but are notlimited to, phenyl, naphthyl, indanyl, anthraquinolyltetrahydronaphthyl, 3,4-methylenedioxyphenyl,1,2,3,4-tetrahydroquinolin-7-yl, 1,2,3,4-tetrahydroisoquinoline-7-yl,and the like.

The term “arylalkyl” or “aralkyl” as used herein denotes the radicalR′R″—, wherein R′ is an aryl radical as defined herein, and R″ is analkylene radical as defined herein with the understanding that theattachment point of the arylalkyl moiety will be on the alkyleneradical. Examples of arylalkyl radicals include, but are not limited to,benzyl, phenylethyl and 3-phenylpropyl.

The term “aryloxy” as used herein denotes an O-aryl group, wherein arylis as defined above. An aryloxy group can be unsubstituted orsubstituted with one or two suitable substituents. The term “phenoxy”refers to an aryloxy group wherein the aryl moiety is a phenyl ring.

The term “thioaryl” as used herein denotes an S-aryl group, wherein arylis as defined above

The term “heteroaryl” or “heteroaromatic” as used herein means amonocyclic or bicyclic radical of 5 to 12 ring atoms having at least onearomatic ring containing four to eight atoms per ring, incorporating oneor more N, O, or S heteroatoms, the remaining ring atoms being carbon,with the understanding that the attachment point of the heteroarylradical will be on an aromatic ring. As well known to those skilled inthe art, heteroaryl rings have less aromatic character than theirall-carbon counter parts. Thus, for the purposes of the invention, aheteroaryl group need only have some degree of aromatic character.Examples of heteroaryl moieties include monocyclic aromatic heterocycleshaving 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is notlimited to, pyridinyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazolyl,imidazolyl, oxazole, isoxazole, thiazole, isothiazole, triazoline,thiadiazole and oxadiaxoline which can optionally be substituted withone or more, preferably one or two substituents selected from hydroxy,cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo,haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino,dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro,alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples ofbicyclic moieties include, but are not limited to, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole,benzothiazole and benzisothiazole. Bicyclic moieties can be optionallysubstituted on either ring.

The term “heteroaryloxy” as used herein means an —O-heteroaryl group,wherein “heteroaryl” is as defined above such as 3-pyridyloxy and2-pyrimidinoxy.

The term “heteroarylalkyl” or “heteroaralkyl” means the radical of theformula R′R″, wherein R′ is an optionally substituted heteroaryl radicalas defined herein, and R″ is an alkylene radical as defined herein withthe understanding that the attachment point of the heteroaryl radicalwill be on the alkylene radical. Examples of heteroarylalky radicalsinclude, but are not limited to, 2-imidazolylmethyl, 3-pyrrolylethyl.

The term “heterocyclyl” or “heterocycle” as used herein denotes amonovalent saturated cyclic radical, consisting of one or more rings,preferably one to two rings, of three to eight atoms per ring,incorporating one or more ring heteroatoms (chosen from N, O orS(O)₀₋₂), and which can optionally be independently substituted with oneor more, preferably one or two substituents selected from hydroxy, oxo,cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo,haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino,alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl,arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unlessotherwise indicated. Examples of heterocyclic radicals include, but arenot limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,oxazolidinyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl,tetrahydropyranyl, thiomorpholinyl, quinuclidinyl.

The term “alkoxy group” as used herein means an —O-alkyl group, whereinalkyl is as defined above such as methoxy, ethoxy, n-propyloxy,i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy,including their isomers. “Lower alkoxy” as used herein denotes an alkoxygroup with a “lower alkyl” group as previously defined. “C₁₋₁₀ alkoxy”as used herein refers to an-O-alkyl wherein alkyl is C₁₋₁₀.

The term “alkylthio” or “thioalkyl” means an —S-alkyl group, whereinalkyl is as defined above such as meththio, ethylthio, n-propylthio,i-propylthio, n-butylthio, hexylthio, including their isomers. “Loweralkylthio” or “lower thioalkyl” as used herein denotes an alkylthiogroup with a “lower alkyl” group as previously defined. “C₁₋₁₀alkylthio” as used herein refers to an-S-alkyl wherein alkyl is C₁₋₁₀.

The terms “alkylsulfonyl” and “arylsulfonyl” as used herein denotes agroup of formula —S(═O)₂R wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein.

The term “halogen” or “halo” as used herein means fluorine, chlorine,bromine, or iodine.

The term “phenylene” as used herein refers to a C₆H₄=radical derivedfrom benzene by replacement of 2H atoms. Three isomers, ortho (o-), meta(m-) and para (p-) are possible.

The term “acyl” as used herein denotes a group of formula —C(═O)Rwherein R is hydrogen or lower alkyl as defined herein. The term or“alkylcarbonyl” as used herein denotes a group of formula C(═O)R whereinR is alkyl as defined herein. The term “arylcarbonyl” as used hereinmeans a group of formula C(═O)R wherein R is an aryl group; the term“benzoyl” as used herein an “arylcarbonyl” group wherein R is phenyl.

Compounds of formula I exhibit tautomerism. Tautomeric compounds canexist as two or more interconvertable species. Prototropic tautomersresult from the migration of a covalently bonded hydrogen atom betweentwo atoms. Tautomers generally exist in equilibrium and attempts toisolate an individual tautomers usually produce a mixture whose chemicaland physical properties are consistent with a mixture of compounds. Theposition of the equilibrium is dependent on chemical features within themolecule. For example, in many aliphatic aldehydes and ketones, such asacetaldehyde, the keto form predominates while; in phenols, the enolform predominates. Common prototropic tautomers include keto/enol(—C(═O)—CH—⇄—C(—OH)═CH—), amide/imidic acid (—C(═O)—NH—⇄—C(—OH)═N—) andamidine (—C(═NR)—NH—⇄—C(—NHR)═N—) tautomers. The latter two areparticularly common in heteroaryl and heterocyclic rings and the presentinvention encompasses all tautomeric forms of the compounds.

It will be appreciated by the skilled artisan that the compounds offormulae Ia and Ib may contain one or more chiral centers and thereforeexist in two or more stereoisomeric forms. The racemates of theseisomers, the individual isomers and mixtures enriched in one enantiomer,as well as diastereomers when there are two chiral centers, and mixturespartially enriched with specific diastereomers are within the scope ofthe present invention. It will be further appreciated by the skilledartisan that substitution of the tropane ring can be in either endo- orexo-configuration, and the present invention covers both configurations.The present invention includes all the individual stereoisomers (e.g.enantiomers), racemic mixtures or partially resolved mixtures of thecompounds of formulae Ia and Ib and, where appropriate, the individualtautomeric forms thereof.

The racemates can be used as such or can be resolved into theirindividual isomers. The resolution can afford stereochemically purecompounds or mixtures enriched in one or more isomers. Methods forseparation of isomers are well known (cf. Allinger N. L. and Eliel E. L.in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) andinclude physical methods such as chromatography using a chiraladsorbent. Individual isomers can be prepared in chiral form from chiralprecursors. Alternatively individual isomers can be separated chemicallyfrom a mixture by forming diasteromeric salts with a chiral acid, suchas the individual enantiomers of 10-camphorsulfonic acid, camphoricacid, .alpha.-bromocamphoric acid, tartaric acid, diacetyltartaric acid,malic acid, pyrrolidone-5-carboxylic acid, and the like, fractionallycrystallizing the salts, and then freeing one or both of the resolvedbases, optionally repeating the process, so as obtain either or bothsubstantially free of the other; i.e., in a form having an opticalpurity of >95%. Alternatively the racemates can be covalently linked toa chiral compound (auxiliary) to produce diastereomers which can beseparated by chromatography or by fractional crystallization after whichtime the chiral auxiliary is chemically removed to afford the pureenantiomers.

The compounds of formulae Ia or Ib contain at least two basic centersand suitable acid addition salts are formed from acids which formnon-toxic salts. Examples of salts of inorganic acids include thechloride, bromide, iodide, sulfate, bisulphate, nitrate, phosphate,hydrogen phosphate. Examples of salts of organic acids include acetate,fumarate, pamoate, aspartate, besylate, carbonate, bicarbonate,camsylate, D and L-lactate, D and L-tartrate, esylate, mesylate,malonate, orotate, gluceptate, methylsulphate, stearate, glucuronate,2-napsylate, tosylate, hibenzate, nicotinate, isethionate, malate,maleate, citrate, gluconate, succinate, saccharate, benzoate and pamoatesalts. For a review on suitable salts see Berge et al, J. Pharm. Sci.,66, 1-19, 1977.

The term “solvate” as used herein means a compound of the invention or asalt, thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for administration to humans in trace amounts.

The term “hydrate” as used herein means a compound of the invention or asalt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

The term “wild type” as used herein refers to the HIV virus strain whichpossesses the dominant genotype which naturally occurs in the normalpopulation which has not been exposed to reverse transcriptaseinhibitors. The term “wild type reverse transcriptase” used herein hasrefers to the reverse transcriptase expressed by the wild type strainwhich has been sequenced and deposited in the SwissProt database with anaccession number PO3366.

The term “reduced susceptibility” as used herein refers to about a 10fold, or greater, change in sensitivity of a particular viral isolatecompared to the sensitivity exhibited by the wild type virus in the sameexperimental system

The term “nucleoside and nucleotide reverse transcriptase inhibitors”(“NRTI”s) as used herein means nucleosides and nucleotides and analoguesthereof that inhibit the activity of HIV-1 reverse transcriptase, theenzyme which catalyzes the conversion of viral genomic HIV-1 RNA intoproviral HIV-1 DNA.

The term “non-nucleoside reverse transcriptase inhibitors” (“NNRTI”s) asused herein means non-nucleosides that inhibit the activity of HIV-1reverse transcriptase.

The term “protease inhibitor” (“PI”) as used herein means inhibitors ofthe HIV-1 protease, an enzyme required for the proteolytic cleavage ofviral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins),into the individual functional proteins found in infectious HIV-1. HIVprotease inhibitors include compounds having a peptidomimetic structure,high molecular weight (7600 daltons) and substantial peptide character,e.g. CRIXIVAN as well as nonpeptide protease inhibitors e.g., VIRACEPT.The following abbreviations are used throughout this specification andclaims: (atm) atmospheres, (BBN or 9-BBN) 9-borabicyclo[3.3.1]nonane,(Boc) tert-butoxycarbonyl, ((BOC)₂O) di-tert-butyl pyrocarbonate or bocanhydride, (Bn) benzyl, (Bu) butyl, (cbz or Z) benzyloxycarbonyl,(DABCO) diazabicyclooctane, (DAST) diethylaminosulfur trifluoride, (DBU)1,8-diazabicyclo[5,4,0]undec-7-ene, (DCE) 1,2-dichloroethane, (DCM)dichloromethane, (DEAD) diethyl azodicarboxylate, (DLAD)di-iso-propylazodicarboxylate, (DEIPA) diethyl iso-propylamine,(DIBAL-H) di-iso-butylaluminumhydride, (DMA) N,N-dimethyl acetamide,(DMAP) 4-N,N-dimethylaminopyridine, (DMF) N,N-dimethylformamide, (dppf)1,1′-bis-(diphenylphosphino)ferrocene, (EDCI)1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (EtOAc)ethyl acetate, (Et₂O) diethyl ether, (Et) ethyl, (EtOH) ethanol,(LiHMDS) lithium hexamethyl disilazane, (HOAc) acetic acid, (HPLC) highpressure liquid chromatography, (i-Pr) iso-propyl, (Me) methyl, (MeCN)acetonitrile, (MeOH) methanol, (MTBE) methyl t-butyl ether, (mp) meltingpoint, (ms) mass spectrum, (NBS) N-bromosuccinimide, (NMP)N-methylpyrrolidone, (PCC) pyridinium chlorochromate, (PDC) pyridiniumdichromate, (Pr) propyl, (psi) pounds per square inch, (pyr) pyridine

(rt or RT) room temperature, (TEA or Et₃N) triethylamine, (Tf) triflateCF₃SO₂—, (TFA) trifluoroacetic acid, (THF) tetrahydrofuran, (TLC) thinlayer chromatography, (TMHD) 2,2,6,6-tetramethylheptane-2,6-dione,(TsOH) p-toluenesulfonic acid monohydrate,

Examples of Compounds of the Invention

Examples of representative compounds encompassed by the presentinvention and within the scope of the invention are provided in thefollowing Table. These examples and preparations which follow areprovided to enable those skilled in the art to more clearly understandand to practice the present invention. They should not be considered aslimiting the scope of the invention, but merely as being illustrativeand representative thereof.

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. If there is a discrepancybetween a depicted structure and a name given that structure, thedepicted structure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it.

Cpd MS # NAME [M + H]⁺ I-14-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-524 3,8-diaza-spiro[4.5]decan-2-one I-24-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diaza- 428spiro[4.5]decan-2-one I-33-Benzyl-4-butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diaza-518 spiro[4.5]decan-2-one I-44-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(tetrahydro-pyran-4-526 ylmethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-54-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-isobutyl-1-oxa-3,8-diaza-484 spiro[4.5]decan-2-one I-64-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(tetrahydro-furan-3-512 ylmethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withhydrochloric acid I-73-Cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-propyl-1-510 oxa-3,8-diaza-spiro[4.5]decan-2-one I-83-Cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-isobutyl-1-524 oxa-3,8-diaza-spiro[4.5]decan-2-one I-94-Cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-468 diaza-spiro[4.5]decan-2-one I-103-Butyl-4-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-524 3,8-diaza-spiro[4.5]decan-2-one I-113-Cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-4- 526ethoxymethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one 1-123-Cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-(2-methoxy-526 ethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-133-Cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-(2-methoxy-526 ethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withhydrochloric acid I-144-But-(E)-ylidene-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-522 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-154-Butyl-3-cyclohexylmethyl-8-[8-(2,6-dimethyl-benzoyl)-8-aza- 550bicyclo[3.2.1]oct-3-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-164-Butyl-3-cyclohexylmethyl-8-[8-(2,6-dimethyl-benzoyl)-8-aza- 550bicyclo[3.2.1]oct-3-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-174-Butyl-3-cyclohexylmethyl-8-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-526 piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-184-Butyl-3-cyclohexylmethyl-8-[1-(2,4-dimethyl-pyridine-3-carbonyl)-piperidin-525 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-194-Butyl-3-cyclohexylmethyl-8-[1-(2-methyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-510 diaza-spiro[4.5]decan-2-one I-204-Butyl-3-cyclohexylmethyl-8-[1-(1,3,5-trimethyl-1H-pyrazole-4-carbonyl)-528 piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-214-Butyl-3-cyclohexylmethyl-8-[1-(4-methoxy-2,6-dimethyl-benzoyl)-piperidin-554 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-224-Butyl-3-cyclohexylmethyl-8-[1-(2,4-dimethyl-6-oxo-6H-pyran-3-carbonyl)-542 piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-234-Butyl-3-cyclohexylmethyl-8-[1-(3,5-dimethyl-isoxazole-4-carbonyl)- 515piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-244-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethoxy-benzoyl)-piperidin-4-yl]-1-556 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-254-Butyl-3-cyclohexylmethyl-8-[1-(3-fluoro-2-methyl-benzoyl)-piperidin-4-yl]-528 1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-264-Butyl-3-cyclohexylmethyl-8-[1-(2,3-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-524 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-274-Butyl-3-cyclohexylmethyl-8-[1-(2,4-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-524 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-284-Butyl-3-cyclohexylmethyl-8-[1-(1-methyl-1H-pyrrole-2-carbonyl)-piperidin-499 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-294-Butyl-3-cyclohexylmethyl-8-[1-(1H-pyrrole-2-carbonyl)-piperidin-4-yl]-1-485 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-304-Butyl-3-cyclohexylmethyl-8-[1-(2-ethyl-5-methyl-2H-pyrazole-3-carbonyl)-528 piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-314-Butyl-3-cyclohexylmethyl-8-[1-(2-methylamino-benzoyl)-piperidin-4-yl]-1-525 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-324-Butyl-3-cyclohexylmethyl-8-[1-(2-dimethylamino-benzoyl)-piperidin-4-yl]-1-539 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-334-Butyl-3-cyclohexylmethyl-8-[1-(2,6-difluoro-benzoyl)-piperidin-4-yl]-1-oxa-532 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-34 8-[1-(1-Acetyl-piperidine-4-carbonyl)-piperidin-4-yl]-4-butyl-3-545 cyclohexylmethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compoundwith trifluoro-acetic acid I-358-(1-Benzoyl-piperidin-4-yl)-4-butyl-3-cyclohexylmethyl-1-oxa-3,8-diaza-496 spiro[4.5]decan-2-one; compound with trifluoro-acetic acid I-364-[4-(4-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-piperidine-1-carbonyl]-benzonitrile; compound with trifluoro-acetic acidI-374-Butyl-8-(1-cyclohexanecarbonyl-piperidin-4-yl)-3-cyclohexylmethyl-1-oxa-521 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-384-Butyl-3-cyclohexylmethyl-8-[1-(furan-2-carbonyl)-piperidin-4-yl]-1-oxa-3,8-486 diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-394-Butyl-3-cyclohexylmethyl-8-[1-(furan-3-carbonyl)-piperidin-4-yl]-1-oxa-3,8-486 diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-404-Butyl-3-cyclohexylmethyl-8-[1-(pyridine-4-carbonyl)-piperidin-4-yl]-1-oxa-497 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-413-[4-(4-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-540 piperidine-1-carbonyl]-benzoic acid; compound with trifluoro-aceticacid I-424-Butyl-3-cyclohexylmethyl-8-[1-(2-trifluoromethyl-benzoyl)-piperidin-4-yl]-1-564 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-434-Butyl-3-cyclohexylmethyl-8-[1-(5-methoxy-1H-indole-2-carbonyl)-piperidin-565 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-444-Butyl-3-cyclohexylmethyl-8-[1-(5-methyl-thiophene-2-carbonyl)-piperidin-4-516 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-454-Butyl-3-cyclohexylmethyl-8-[1-(thiophene-3-carbonyl)-piperidin-4-yl]-1-oxa-502 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-464-Butyl-3-cyclohexylmethyl-8-[1-(pyridine-2-carbonyl)-piperidin-4-yl]-1-oxa-497 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-474-Butyl-3-cyclohexylmethyl-8-[1-(2-methyl-pyridine-3-carbonyl)-piperidin-4-511 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-484-Butyl-3-cyclohexylmethyl-8-[1-(3-methyl-furan-2-carbonyl)-piperidin-4-yl]-500 1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-494-Butyl-3-cyclohexylmethyl-8-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-1-oxa-497 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-504-Butyl-3-cyclohexylmethyl-8-[1-(pyrazine-2-carbonyl)-piperidin-4-yl]-1-oxa-498 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-514-Butyl-8-[1-(2-chloro-benzoyl)-piperidin-4-yl]-3-cyclohexylmethyl-1-oxa-3,8-530 diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-524-Butyl-3-cyclohexylmethyl-8-[1-(5-methyl-isoxazole-4-carbonyl)-piperidin-4-501 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-534-Butyl-3-cyclohexylmethyl-8-[1-(2-methyl-thiazole-4-carbonyl)-piperidin-4-517 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-544-Butyl-3-cyclohexylmethyl-8-[1-(1-methyl-1H-pyrazole-3-carbonyl)-piperidin-500 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-554-Butyl-3-cyclohexylmethyl-8-[1-(1-methyl-1H-imidazole-2-carbonyl)- 500piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-564-Butyl-3-cyclohexylmethyl-8-[1-(tetrahydro-furan-2-carbonyl)-piperidin-4-yl]-490 1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-574-Butyl-3-cyclohexylmethyl-8-[1-(4-methoxy-thiophene-3-carbonyl)-piperidin-532 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-584-Butyl-3-cyclohexylmethyl-8-[1-(3-methyl-pyridine-2-carbonyl)-piperidin-4-511 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-594-Butyl-3-cyclohexylmethyl-8-[1-(1H-pyrazole-4-carbonyl)-piperidin-4-yl]-1-486 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-604-Butyl-3-cyclohexylmethyl-8-{1-[2-(1-methyl-1H-imidazol-4-yl)-acetyl]-514 piperidin-4-yl}-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-614-Butyl-3-cyclohexylmethyl-8-(1-phenylacetyl-piperidin-4-yl)-1-oxa-3,8-diaza-510 spiro[4.5]decan-2-one; compound with trifluoro-acetic acid I-624-Butyl-3-cyclohexylmethyl-8-[1-(2-imidazol-1-yl-acetyl)-piperidin-4-yl]-1-500 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-634-Butyl-3-cyclohexylmethyl-8-[1-(3-morpholin-4-yl-propionyl)-piperidin-4-yl]-533 1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-644-Butyl-3-cyclohexylmethyl-8-{1-[3-(4-methyl-piperazin-1-yl)-propionyl]-546 piperidin-4-yl}-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-654-Butyl-3-cyclohexylmethyl-8-[1-(2-1H-tetrazol-5-yl-acetyl)-piperidin-4-yl]-1-502 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-664-Butyl-3-cyclohexylmethyl-8-[1-(3-pyridin-3-yl-propionyl)-piperidin-4-yl]-1-525 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-674-(4-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-526 piperidine-1-carboxylic acid benzyl ester I-684-Butyl-3-cyclohexylmethyl-8-[1-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperidin-551 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-694-Butyl-8-[1-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-piperidin-4-yl]-3-584 cyclohexylmethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compoundwith trifluoro-acetic acid I-704-[4-(4-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-608 piperidine-1-sulfonyl]-2,5-dimethyl-furan-3-carboxylic acid methylester; compound with trifluoro-acetic acid I-718-(1-Benzenesulfonyl-piperidin-4-yl)-4-butyl-3-cyclohexylmethyl-1-oxa-3,8-532 diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-724-Butyl-3-cyclohexylmethyl-8-[1-(thiophene-2-sulfonyl)-piperidin-4-yl]-1-oxa-538 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-734-Butyl-3-cyclohexylmethyl-8-[1-(2,4,6-trimethyl-benzenesulfonyl)-piperidin-574 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-744-(4-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-539 piperidine-1-carboxylic acid (2,6-dimethyl-phenyl)-amide; compoundwith trifluoro-acetic acid I-751-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1,4,9-662 triaza-spiro[5.5]undecane-2,5-dione I-761-Butyl-3-((S)-cyclohexyl-hydroxy-methyl)-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1,4,9-triaza-spiro[5.5]undecane-2,5-dione (m.p.246.9-248) I-775-Butyl-3-methyl-9-(1-[(E)-3-(3,4,5-trimethoxy-phenyl)-acryloyl]-piperidin-4-544 yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-784-(5-Butyl-3-methyl-2-oxo-1-oxa-3,9-diaza-spiro[5.5]undec-9-yl)-piperidine-1-471 carboxylic acid (2,6-dimethyl-phenyl)-amide; compound withtrifluoro-acetic acid I-798-[1-(2,6-Dimethyl-benzoyl)-piperidin-4-yl]-3-phenethyl-1-oxa-3,8-diaza-476 spiro[4.5]decan-2-one; compound with trifluoro-acetic acid I-804-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-4-methyl-piperidin-4- 538yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with hydrochloricacid I-814-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-methoxy-ethyl)-1-486 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoroaceticacid I-824-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-ethyl-1-oxa-3,8-diaza-456.7 spiro[4.5]decan-2-one; compound with methane I-834-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-phenethyl-1-oxa-3,8-532.6 diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-844-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-fluoro-ethyl)-1-oxa-474.7 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-854-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-hexyl-1-oxa-3,8-diaza-512.8 spiro[4.5]decan-2-one; compound with trifluoro-acetic acid I-864-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-((S)-2-methyl-butyl)-1-498.8 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-874-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(3-methyl-butyl)-1-oxa-498.8 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-884-Butyl-3-cyclopropylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-482.2 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-894-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(5-methyl-hexyl)-1-oxa-526.8 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-904-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-methyl-butyl)-1-oxa-512.8 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-914-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-pentyl-1-oxa-3,8-diaza-498.8 spiro[4.5]decan-2-one; compound with trifluoro-acetic acid I-924-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-methyl-benzyl)-1-532.8 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-934-Butyl-3-(2-cyclohexyl-ethyl)-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-538.9 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-944-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-fluoro-benzyl)-1-oxa-536.8 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-954-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(1-phenyl-ethyl)-1-oxa-532.8 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-964-Butyl-3-cyclobutylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-496.8 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-974-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-hydroxy-ethyl)-1-472.8 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-984-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-hydroxy-ethyl)-1-500.9 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-998-[1-(2,6-Dimethyl-benzoyl)-piperidin-4-yl]-4-methyl-3-(tetrahydro-furan-2-512 ylmethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro- acetic acid I-1004-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-hydroxy-ethyl)-1-472.8 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1014-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-hydroxy-ethyl)-1-500.9 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1024-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-methoxy-ethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-1038-[1-(2,6-Dimethyl-benzoyl)-piperidin-4-yl]-4-methyl-3-(tetrahydro-furan-2-ylmethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro- acetic acid I-1044-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(4-fluoro-2- 604.7trifluoromethyl-benzyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compoundwith trifluoro-acetic acid I-1054-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-trifluoromethyl-586.7 benzyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1064-Butyl-3-(2,6-difluoro-benzyl)-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-554.7 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1074-Butyl-3-(2-diethylamino-ethyl)-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-527.7 1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1084-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-methoxy-ethyl)-1-486.7 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1094-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-propyl-1-oxa-3,8-diaza-470.7 spiro[4.5]decan-2-one; compound with trifluoro-acetic acid I-1103,4-Dibutyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diaza-484.7 spiro[4.5]decan-2-one; compound with trifluoro-acetic acid I-1114-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-pyridin-3-ylmethyl-1-519.7 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1122-{4-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-2-oxo-1-oxa-3,8-diaza-566.7 spiro[4.5]dec-3-ylmethyl}-furan-3-carboxylic acid methyl ester;compound with trifluoro-acetic acid I-1132-{4-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-2-oxo-1-oxa-3,8-diaza-541.7 spiro[4.5]dec-3-yl}-N,N-diethyl-acetamide; compound withtrifluoro-acetic acid I-1144-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-methoxy-benzyl)-1-548.7 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1154-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-pyridin-4-ylmethyl-1-519.7 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1164-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-pyridin-2-ylmethyl-1-519.7 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1174-Butyl-3-(2-dimethylamino-ethyl)-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-499.7 1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1184-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-morpholin-4-yl-541.7 ethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1194-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-piperidin-1-yl-ethyl)-539.7 1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1204-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-pyrrolidin-1-yl-ethyl)-525.9 1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1214-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-[2-(1-methyl-pyrrolidin-539.7 2-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro- acetic acid I-1222-{4-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-2-oxo-1-oxa-3,8-diaza-513.7 spiro[4.5]dec-3-yl}-N,N-dimethyl-acetamide; compound withtrifluoro-acetic acid I-1234-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-methyl-thiazol-4-539.7 ylmethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro- acetic acid I-1243-(2-tert-Butoxy-ethyl)-4-butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-528.8 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1254-Butyl-3-cyclopentylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-510.7 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1264-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-4-morpholin-4-yl-benzoyl)-609.8 piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compoundwith trifluoro-acetic acid I-1274-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-thiazol-4-ylmethyl-1-525.8 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1284-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-pyrrol-1-yl-ethyl)-1-521.8 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1294-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(4-methyl-pent-3-enyl)-510.8 1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1304-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(1-methyl-butyl)-1-oxa-498.8 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-1314-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(tetrahydro-pyran-2-526.7 ylmethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro- acetic acid I-1324-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-ethoxy-ethyl)-1-oxa-500.7 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-1334-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-[2-(2-methoxy-ethoxy)-530.7 ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1344-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(3,5-dimethyl-isoxazol-537.7 4-ylmethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro- acetic acid I-1354-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(5-methyl-isoxazol-3-523.7 ylmethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro- acetic acid I-1364-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(3-methyl-pyridin-2-533.8 ylmethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro- acetic acid I-1374-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(4-fluoro-butyl)-1-oxa-502.7 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-1384-Butyl-3-cyclohexylmethyl-8-[1-(4-fluoro-2,6-dimethyl-benzoyl)-piperidin-4-542.8 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1394-[4-(4-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-567.8 piperidine-1-carbonyl]-3,5-dimethyl-benzamide; compound withtrifluoro-acetic acid I-1404-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-4-pyridin-4-yl-benzoyl)-601.3 piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compoundwith trifluoro-acetic acid I-1414-[4-(5-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,9-diaza-spiro[5.5]undec-9-yl)-582.4 piperidine-1-carbonyl]-3,5-dimethyl-benzoic acid; compound withtrifluoro- acetic acid I-1425-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-4-pyridin-4-yl-benzoyl)-615.6 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-1434-[4-(5-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,9-diaza-spiro[5.5]undec-9-yl)-610.6 piperidine-1-carbonyl]-3,5-dimethyl-benzoic acid ethyl ester;compound with trifluoro-acetic acid I-1445-Butyl-3-cyclohexylmethyl-9-[1-(4-iodo-2,6-dimethyl-benzoyl)-piperidin-4-664.5 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-1455-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-4-thiophen-2-yl-benzoyl)-620.7 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-1464-[4-(5-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,9-diaza-spiro[5.5]undec-9-yl)-563.6 piperidine-1-carbonyl]-3,5-dimethyl-benzonitrile; compound withtrifluoro- acetic acid I-1475-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-4-pyridin-3-yl-benzoyl)-615.6 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-1485-Butyl-3-cyclohexylmethyl-9-{1-[2,6-dimethyl-4-(4-methyl-thiazol-5-yl)-635.6 benzoyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-149{4-[4-(4-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-647 piperidine-1-carbonyl]-3,5-difluoro-phenyl}-carbamic acid tert-butylester I-1508-[1-(4-Amino-2,6-difluoro-benzoyl)-piperidin-4-yl]-4-butyl-3- 547cyclohexylmethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-151N-{4-[4-(4-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-589 yl)-piperidine-1-carbonyl]-3,5-difluoro-phenyl}-acetamide I-1522-[4-(4-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-535 piperidine-1-carbonyl]-3-methyl-benzonitrile I-1532-[4-(5-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,9-diaza-spiro[5.5]undec-9-yl)-549 piperidine-1-carbonyl]-3-methyl-benzonitrile I-1545-But-3-enyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-536 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1555-Butyl-3-cyclohexylmethyl-9-[4-methyl-1-(2,4,5-trimethyl-thiophene-3-572 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-oneI-1565-Butyl-3-cyclohexylmethyl-9-[4-methyl-1-(5-methyl-3-phenyl-isoxazole-4-605 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-1575-Butyl-9-{1-[4,6-dimethyl-2-(pyridin-2-yloxy)-pyrimidine-5-carbonyl]-537 piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-1584-Butyl-3-cyclohexylmethyl-8-[1-(3,5-dichloro-pyridine-4-carbonyl)-piperidin-565 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-159(S)-4-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-524 oxa-3,8-diaza-spiro[4.5]decan-2-one I-160(R)-4-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-524 oxa-3,8-diaza-spiro[4.5]decan-2-one I-1614-Butyl-3-cyclohexylmethyl-8-[1-(3,5-dichloro-pyridine-4-carbonyl)-piperidin-581 4-yl]-8-oxy-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-1624-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(1-hydroxy- 540cyclohexylmethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-1634-Butyl-3-cyclohexylmethyl-8-[1-(4-methoxy-2,6-dimethyl-benzoyl)-piperidin-570 4-yl]-8-oxy-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-1645-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(1-hydroxy- 554cyclohexylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1655-Butyl-3-cyclohexanecarbonyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-552 oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1661-{5-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-2-oxo-1-oxa-3,9-diaza-563 spiro[5.5]undec-3-ylmethyl}-cyclohexanecarbonitrile I-167(E)-4-{3-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-2-oxo-580 1-oxa-3,9-diaza-spiro[5.5]undec-5-yl}-but-2-enoic acid methyl esterI-168(E)-4-{3-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-2-oxo-547 1-oxa-3,9-diaza-spiro[5.5]undec-5-yl}-but-2-enenitrile I-1694-{3-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-2-oxo-1-582 oxa-3,9-diaza-spiro[5.5]undec-5-yl}-butyric acid methyl ester I-1704-{3-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-2-oxo-1-549 oxa-3,9-diaza-spiro[5.5]undec-5-yl}-butyronitrile I-1713-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-((E)-4-oxo-564 pent-2-enyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-172(E)-4-(3-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-2-oxo-566 1-oxa-3,9-diaza-spiro[5.5]undec-5-yl}-but-2-enoic acid I-1733-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-((E)-4-566 hydroxy-pent-2-enyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1743-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-(4-oxo-566 pentyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1754-(3-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-2-oxo-1-568 oxa-3,9-diaza-spiro[5.5]undec-5-yl}-butyric acid I-1763-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-(4-hydroxy-568 pentyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-177{3-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-2-oxo-1-oxa-539 3,9-diaza-spiro[5.5]undec-5-yl}-acetaldehyde oxime I-1783-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-((E)-pent-2-550 enyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1793-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-pentyl-1-552 oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1803-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-((E)-3-600 methanesulfonyl-allyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1813-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-(2-methoxy-540 ethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1823-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-(3- 602methanesulfonyl-propyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1835-Allyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-522 3,9-diaza-spiro[5.5]undecan-2-one I-1843-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-propyl-1-524 oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1853-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-(3,3,3-594 trifluoro-2-hydroxy-propyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-oneI-1863-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-(3,3,3-594 trifluoro-2-hydroxy-propyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-oneI-1873-Cyclohexylmethyl-5-(2-cyclopropyl-ethyl)-9-[1-(2,6-dimethyl-benzoyl)-550 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1887-[4-(5-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,9-diaza-spiro[5.5]undec-9-yl)-651 piperidine-1-carbonyl]-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester I-1895-Butyl-3-cyclohexylmethyl-9-[1-(2,3-dihydro-1H-indole-7-carbonyl)- 551piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-190(R)-5-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-538 oxa-3,9-diaza-spiro[5.5]undecan-2-one I-191(S)-5-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-538 oxa-3,9-diaza-spiro[5.5]undecan-2-one I-1924-Butyl-3-methyl-8-[1-(2,4,6-trimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-456.8 diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-1934-Butyl-8-[1-(2,6-dichloro-benzoyl)-piperidin-4-yl]-3-methyl-1-oxa-3,8-diaza-482.7 spiro[4.5]decan-2-one; compound with trifluoro-acetic acid I-1944-Butyl-8-[1-(2-chloro-6-methyl-benzoyl)-piperidin-4-yl]-3-methyl-1-oxa-3,8-462.7 diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-1954-Butyl-8-[1-(2,6-dichloro-4-methyl-benzoyl)-piperidin-4-yl]-3-methyl-1-oxa-469.7 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-1964-Butyl-8-[1-(4-methoxy-2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-methyl-1-472.8 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-1978-[1-(4-Butoxy-2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-butyl-3-methyl-1-oxa-514.8 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-1984-Butyl-8-[1-(4-ethoxy-2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-methyl-1-oxa-486.8 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-1994-Butyl-8-[1-(2-chloro-6-fluoro-benzoyl)-piperidin-4-yl]-3-methyl-1-oxa-3,8-466.7 diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-2008-[1-(2-Bromo-6-methyl-benzoyl)-piperidin-4-yl]-4-butyl-3-methyl-1-oxa-3,8-508.7 diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-2014-Butyl-8-[1-(2,6-difluoro-4-methoxy-benzoyl)-piperidin-4-yl]-3-methyl-1-oxa-480.7 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-aceticacid I-2024-Butyl-3-methyl-8-[1-(2,4,6-trimethoxy-benzoyl)-piperidin-4-yl]-1-oxa-3,8-504.8 diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-2034-Butyl-8-[1-(2,3-dimethyl-benzoyl)-piperidin-4-yl]-3-methyl-1-oxa-3,8-diaza-442.8 spiro[4.5]decan-2-one; compound with trifluoro-acetic acid I-2044-Butyl-8-[1-(2,4-dimethyl-benzoyl)-piperidin-4-yl]-3-methyl-1-oxa-3,8-diaza-442.8 spiro[4.5]decan-2-one; compound with trifluoro-acetic acid I-2054-Butyl-8-[1-(2-dimethylamino-benzoyl)-piperidin-4-yl]-3-methyl-1-oxa-3,8-45738 diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-2064-Butyl-3-methyl-8-[1-(1H-pyrrole-2-carbonyl)-piperidin-4-yl]-1-oxa-3,8-403.7 diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-2074-Butyl-8-[1-(3,5-dimethyl-isoxazole-4-carbonyl)-piperidin-4-yl]-3-methyl-1-433.8 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-2084-Butyl-8-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-piperidin-4-yl]-3-methyl-1-444.8 oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-2098-[1-(4-Butoxy-2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-butyl-3- 596.9cyclohexylmethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-2104-Butyl-3-cyclohexylmethyl-8-[1-(4-hydroxy-2,6-dimethyl-benzoyl)-piperidin-540 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with compoundwith hydrochloric acid I-2114-Butyl-3-cyclohexylmethyl-8-[1-(4-ethoxy-2,6-dimethyl-benzoyl)-piperidin-4-568 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound with compoundwith hydrochloric acid I-2124-Butyl-3-cyclohexylmethyl-8-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-540.8 methyl-piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;compound with trifluoro-acetic acid I-2134-Butyl-3-cyclohexylmethyl-8-[1-(2,4-dimethyl-pyridine-3-carbonyl)-4-methyl-539.8 piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compoundwith trifluoro-acetic acid I-2148-[1-(1-Benzyl-3,5-dimethyl-1H-pyrazole-4-carbonyl)-4-methyl-piperidin-4-618.9yl]-4-butyl-3-cyclohexylmethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;compound with trifluoro-acetic acid I-2154-Butyl-3-cyclohexylmethyl-8-[1-(3,5-dimethyl-1-phenyl-1H-pyrazole-4-604.8carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;compound with trifluoro-acetic acid I-2164-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dichloro-benzoyl)-4-methyl-piperidin-4-578.7 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-2178-[1-(4-Benzyloxy-2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-butyl-3- 630.9cyclohexylmethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withhydrochloric acid I-2184-Butyl-3-cyclohexylmethyl-8-[1-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-577.7 piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compoundwith trifluoro-acetic acid I-2194-Butyl-3-cyclohexylmethyl-8-[1-(3-methyl-thiophene-2-carbonyl)-piperidin-4-516.6 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-2204-Butyl-3-cyclohexylmethyl-8-[1-(2-methyl-2H-pyrazole-3-carbonyl)- 500.7piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-2214-Butyl-3-cyclohexylmethyl-8-[1-(2-methyl-5-propyl-2H-pyrazole-3-carbonyl)-542.7 piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compoundwith trifluoro-acetic acid I-2224-Butyl-3-cyclohexylmethyl-8-[1-(4-methyl-2-phenyl-thiazole-5-carbonyl)-593.9 piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compoundwith trifluoro-acetic acid I-2234-Butyl-3-cyclohexylmethyl-8-[1-(4-methyl-2-pyridin-3-yl-thiazole-5-594.7 carbonyl)-piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;compound with trifluoro-acetic acid I-2244-Butyl-3-cyclohexylmethyl-8-[1-(3,5-dimethyl-1H-pyrrole-2-carbonyl)-513.7 piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compoundwith trifluoro-acetic acid I-2254-Butyl-3-cyclohexylmethyl-8-[1-(5-ethyl-2-methyl-2H-pyrazole-3-carbonyl)-528.7 piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compoundwith trifluoro-acetic acid I-2264-Butyl-3-cyclohexylmethyl-8-[1-(4-methyl-thiazole-5-carbonyl)-piperidin-4-517.7 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-2274-Butyl-3-cyclohexylmethyl-8-[1-(2,4-dimethyl-thiazole-5-carbonyl)-piperidin-531.7 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compound withtrifluoro-acetic acid I-2285-[4-(4-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-578.7 piperidine-1-carbonyl]-1-methyl-1H-pyrrole-2-sulfonic acid amide;compound with trifluoro-acetic acid I-2294-Butyl-3-cyclohexylmethyl-8-{1-[4-(2-methoxy-ethoxy)-2,6-dimethyl-598.8 benzoyl]-piperidin-4-yl}-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;compound with trifluoro-acetic acid I-2305-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dichloro-benzoyl)-piperidin-4-yl]-1-oxa-578.6 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-2315-Butyl-9-[1-(2-chloro-6-methyl-benzoyl)-piperidin-4-yl]-3-cyclohexylmethyl-558.7 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2325-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dichloro-4-methyl-benzoyl)-piperidin-4-592.7 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2335-Butyl-3-cyclohexylmethyl-9-[1-(4-methoxy-2,6-dimethyl-benzoyl)-piperidin-568.8 4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2349-[1-(4-Butoxy-2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-butyl-3- 610.8cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2355-Butyl-3-cyclohexylmethyl-9-[1-(4-ethoxy-2,6-dimethyl-benzoyl)-piperidin-4-582.8 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2365-Butyl-9-[1-(2-chloro-6-fluoro-benzoyl)-piperidin-4-yl]-3-cyclohexylmethyl-562.7 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2375-Butyl-3-cyclohexylmethyl-9-[1-(2,4,6-trimethyl-benzoyl)-piperidin-4-yl]-1-552.8 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2389-[1-(2-Bromo-6-methyl-benzoyl)-piperidin-4-yl]-5-butyl-3-cyclohexylmethyl-602.7 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2395-Butyl-3-cyclohexylmethyl-9-[1-(2,6-difluoro-4-methoxy-benzoyl)-piperidin-576.8 4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2404-[4-(5-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,9-diaza-spiro[5.5]undec-9-583.8 yl)-piperidine-1-carbonyl]-3,5-dimethyl-benzamide; compound withtrifluoro- acetic acid I-2415-Butyl-9-[1-(4-chloro-2-methoxy-benzoyl)-piperidin-4-yl]-3- 574.8cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2425-Butyl-3-cyclohexylmethyl-9-[1-(2,3-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-538.8 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-2435-Butyl-3-cyclohexylmethyl-9-[1-(2,4-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-538.8 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-2445-Butyl-3-cyclohexylmethyl-9-[1-(2-methoxy-4-methylsulfanyl-benzoyl)-586.8 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-2455-Butyl-3-cyclohexylmethyl-9-[1-(2-dimethylamino-benzoyl)-piperidin-4-yl]-1-553.8 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2465-Butyl-3-cyclohexylmethyl-9-[1-(3,5-dimethyl-isoxazole-4-carbonyl)-529.8 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-2475-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-540.8 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-2489-[1-(2-Bromo-6-fluoro-benzoyl)-piperidin-4-yl]-5-butyl-3-cyclohexylmethyl-606.6 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2499-[1-(1-Benzyl-3,5-dimethyl-1H-pyrazole-4-carbonyl)-piperidin-4-yl]-5-butyl-618.8 3-cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-2509-[1-(5-Acetyl-2,4-dimethyl-1H-pyrrole-3-carbonyl)-piperidin-4-yl]-5-butyl-3-569.8 cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-2515-Butyl-3-cyclohexylmethyl-9-[1-(2,4,6-trimethoxy-benzoyl)-piperidin-4-yl]-1-600.8 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2525-Butyl-9-[1-(3-chloro-2,6-dimethoxy-benzoyl)-piperidin-4-yl]-3- 604.8cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2535-Butyl-3-cyclohexylmethyl-9-[1-(2-fluoro-6-methoxy-benzoyl)-piperidin-4-558.8 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2545-Butyl-3-cyclohexylmethyl-9-[1-(3,6-dichloro-2-methoxy-benzoyl)-piperidin-608.8 4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2555-Butyl-3-cyclohexylmethyl-9-[1-(3,5-dimethyl-1-phenyl-1H-pyrazole-4-604.9 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-2565-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethoxy-3-nitro-benzoyl)-piperidin-4-615.8 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-onetrifluoro-acetic acid;I-2575-Butyl-3-cyclohexylmethyl-9-[1-(2,4,6-trichloro-benzoyl)-piperidin-4-yl]-1-612.7 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2585-Butyl-9-[1-(3-chloro-2,6-difluoro-benzoyl)-piperidin-4-yl]-3- 580.8cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2595-Butyl-9-[1-(2-chloro-3,6-difluoro-benzoyl)-piperidin-4-yl]-3- 580.8cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2605-Butyl-3-cyclohexylmethyl-9-[1-(2-fluoro-6-trifluoromethyl-benzoyl)-596.8 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-2615-Butyl-9-[1-(6-chloro-2-fluoro-3-methyl-benzoyl)-piperidin-4-yl]-3-576.8 cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-2625-Butyl-9-[1-(2-chloro-6-fluoro-3-methyl-benzoyl)-piperidin-4-yl]-3-576.8 cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-2635-Butyl-3-cyclohexylmethyl-9-[1-(2,4,6-trifluoro-benzoyl)-piperidin-4-yl]-1-564.8 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2645-Butyl-9-[1-(3-chloro-2-fluoro-6-trifluoromethyl-benzoyl)-piperidin-4-yl]-3-630.8 cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-2655-Butyl-3-cyclohexylmethyl-9-[1-(2,3,6-trifluoro-benzoyl)-piperidin-4-yl]-1-564.8 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2665-Butyl-9-[1-(2-chloro-6-nitro-benzoyl)-piperidin-4-yl]-3-cyclohexylmethyl-1-589.8 oxa-3,9-diaza-spiro[5.5]undecan-2-onetrifluoro-acetic acid; I-2675-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-ethyl-1-oxa-3,9-diaza-470.7 spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-2685-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-phenethyl-1-oxa-3,9-546.7 diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acidI-2695-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-fluoro-ethyl)-1-oxa-488.7 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-2705-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-((S)-2-methyl-butyl)-1-512.7 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2715-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(3-methyl-butyl)-1-oxa-512.7 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-2725-Butyl-3-cyclopropylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-496.7 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2735-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-ethyl-butyl)-1-oxa-526.7 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-2745-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-methyl-benzyl)-1-546.7 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2755-Butyl-3-(2-cyclohexyl-ethyl)-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-552.8 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2765-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-fluoro-benzyl)-1-oxa-550.7 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-2775-Butyl-3-cyclobutylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-510.7 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-2785-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-methoxy-ethyl)-1-500.8 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2795-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-propyl-1-oxa-3,9-diaza-484.8 spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-2803,5-Dibutyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,9-diaza-498.8 spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-2815-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-pyridin-4-ylmethyl-1-533.8 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2825-Butyl-3-(2-dimethylamino-ethyl)-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-513.8 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2835-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-morpholin-4-yl-555.8 ethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2845-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-piperidin-1-yl-ethyl)-553.8 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2855-Butyl-3-cyclopentylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-524.8 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2865-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(tetrahydro-pyran-4-540.8 ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro- acetic acid I-2875-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-pyridin-3-ylmethyl-1-533.4 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2885-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-pyridin-2-ylmethyl-1-533.4 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2895-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(tetrahydro-furan-2-526.4 ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro- acetic acid I-2905-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-[1,3]dioxolan-2-528.4 ylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro- acetic acid I-2915-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(tetrahydro-pyran-2-540.4 ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro- acetic acid I-2925-Butyl-3-cyclohexylmethyl-9-[1-(2,4-dimethyl-pyridine-3-carbonyl)-piperidin-539.4 4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2935-Butyl-3-cyclohexylmethyl-9-[1-(2,4,5-trimethyl-thiophene-3-carbonyl)-558.6 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-2945-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(tetrahydro-furan-3-523.4 ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro- acetic acid I-2955-Butyl-3-cyclohexylmethyl-9-[1-(6-hydroxy-2,4-dimethyl-pyridine-3-555.4 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-2969-[1-(4-Amino-2,6-difluoro-benzoyl)-piperidin-4-yl]-5-butyl-3- 561.4cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2975-Butyl-3-cyclohexylmethyl-9-[1-(2-methoxy-4,6-dimethyl-pyrimidine-5-570.4 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-2985-Butyl-3-cyclohexylmethyl-9-[1-(4-fluoro-2,6-dimethyl-benzoyl)-piperidin-4-556.4 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-2995-Butyl-3-cyclohexylmethyl-9-[1-(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-555.4piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-onetrifluoro-aceticacid; I-3005-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-2-methylsulfanyl-pyrimidine-586.45-carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3015-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-1-oxy-pyrimidine-5-carbonyl)-556.4piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-onetrifluoro-aceticacid; I-3025-Butyl-3-cyclohexylmethyl-9-[1-(2,3-dihydro-1H-indole-7-carbonyl)-551.5 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3035-Butyl-3-cyclohexylmethyl-9-[1-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-591.3 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3045-Butyl-3-cyclohexylmethyl-9-{1-[3-(2,6-dichloro-phenyl)-5-methyl-isoxazole-659.24-carbonyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3059-[1-(Biphenyl-2-carbonyl)-piperidin-4-yl]-5-butyl-3-cyclohexylmethyl-1-oxa-586.3 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-3065-Butyl-3-cyclohexylmethyl-9-[1-(2-methyl-naphthalene-1-carbonyl)-piperidin-574.4 4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3075-Butyl-9-{1-[3-(2-chloro-phenyl)-5-methyl-isoxazo1e-4-carbonyl]-piperidin-625.4 4-yl}-3-cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3085-Butyl-3-cyclohexylmethyl-9-[1-(1,2,3,4-tetrahydro-acridine-9-carbonyl)-615.4 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3095-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dichloro-4-methanesulfonyl-benzoyl)-656.4 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3105-Butyl-3-cyclohexylmethyl-9-[1-(quinoline-3-carbonyl)-piperidin-4-yl]-1-oxa-561.4 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-3115-Butyl-3-cyclohexylmethyl-9-[1-(quinoline-4-carbonyl)-piperidin-4-yl]-1-oxa-561.4 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-3125-Butyl-3-cyclohexylmethyl-9-[1-(quinoline-6-carbonyl)-piperidin-4-yl]-1-oxa-561.4 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-3135-Butyl-3-cyclohexylmethyl-9-[1-(2-morpholin-4-yl-benzoyl)-piperidin-4-yl]-1-595.5 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3145-Butyl-3-cyclohexylmethyl-9-[1-(2-morpholin-4-yl-5-pyrrol-1-yl-benzoyl)-660.6 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3155-Butyl-3-cyclohexylmethyl-9-[1-(quinoline-8-carbonyl)-piperidin-4-yl]-1-oxa-561.5 3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-aceticacid I-3165-Butyl-3-cyclohexylmethyl-9-[1-(2-methyl-quinoline-3-carbonyl)-piperidin-4-575.5 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3175-Butyl-9-[1-(2-chloro-4-methyl-6-pyrrolidin-1-yl-benzoyl)-piperidin-4-yl]-3-627.5 cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3185-Butyl-3-cyclohexylmethyl-9-{1-[2-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-643.6 benzoyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3199-[1-(5-Amino-1-phenyl-1H-pyrazole-4-carbonyl)-piperidin-4-yl]-5-butyl-3-591.6 cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3209-{1-[5-Amino-1-(4-methoxy-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-621.6yl}-5-butyl-3-cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3215-Butyl-3-cyclohexylmethyl-9-[1-(1-phenyl-5-trifluoromethyl-1H-pyrazole-4-644.6 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3225-Butyl-3-cyclohexylmethyl-9-{1-[1-(4-methoxy-phenyl)-5-trifluoromethyl-674.61H-pyrazole-4-carbonyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-3235-Butyl-3-cyclohexylmethyl-9-{1-[1-(2-methoxy-phenyl)-5-trifluoromethyl-674.61H-pyrazole-4-carbonyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-3245-Butyl-3-cyclohexylmethyl-9-{1-[2-(4-fluoro-benzyl)-5-methyl-2H-pyrazole-622.63-carbonyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3255-Butyl-9-{1-[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-678.6piperidin-4-yl}-3-cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3265-Butyl-3-cyclohexylmethyl-9-[1-(1-p-tolyl-5-trifluoromethyl-1H-pyrazole-4-658.6 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3275-Butyl-3-cyclohexylmethyl-9-{1-[1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-662.6pyrazole-4-carbonyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3289-[1-(5-Amino-1-p-tolyl-1H-pyrazole-4-carbonyl)-piperidin-4-yl]-5-butyl-3-605.6 cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3299-{1-[5-Amino-1-(4-fluoro-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-yl}-5-609.6 butyl-3-cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3309-{1-[5-Amino-1-(2-methoxy-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-621.6yl}-5-butyl-3-cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3315-Butyl-3-cyclohexylmethyl-9-[1-(5-methyl-1-phenyl-1H-pyrazole-4-carbonyl)-590.6 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3325-Butyl-3-cyclohexylmethyl-9-[1-(5-methyl-1-p-tolyl-1H-pyrazole-4-carbonyl)-604.6 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3335-Butyl-9-{1-[1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-624.6piperidin-4-yl}-3-cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3345-Butyl-3-cyclohexylmethyl-9-[1-(5-methyl-2-p-tolyl-2H-pyrazole-3-carbonyl)-604.6 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3355-Butyl-3-cyclohexylmethyl-9-{1-[2-(4-methoxy-phenyl)-5-methyl-2H- 620.6pyrazole-3-carbonyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3365-Butyl-3-cyclohexylmethyl-9-[1-(2-methyl-4,5,6,7-tetrahydro-benzofuran-3-568.6 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3375-Butyl-3-cyclohexylmethyl-9-[1-(3,5-dimethyl-1H-pyrazole-4-carbonyl)-528.6 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3389-[1-(2-Bromo-pyridine-3-carbonyl)-piperidin-4-yl]-5-butyl-3- 589.5cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3395-Butyl-3-cyclohexylmethyl-9-[1-(2-fluoro-pyridine-3-carbonyl)-piperidin-4-529.6 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3405-Butyl-9-[1-(3-chloro-pyridine-4-carbonyl)-piperidin-4-yl]-3- 545.6cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3415-Butyl-3-cyclohexylmethyl-9-[1-(2-methoxy-pyridine-3-carbonyl)-piperidin-4-541.6 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3425-Butyl-3-cyclohexylmethyl-9-[1-(2-methanesulfonyl-benzoyl)-piperidin-4-yl]-588.6 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3435-Butyl-3-cyclohexylmethyl-9-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-594.6 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-344N-{2-[4-(5-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,9-diaza-spiro[5.5]undec-603.6 9-yl)-piperidine-1-carbonyl]-phenyl}-methanesulfonamide; compoundwith trifluoro-acetic acid I-3455-Butyl-3-cyclohexylmethyl-9-[1-(2-methyl-5-trifluoromethyl-oxazole-4-583.6 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3469-[1-(2-Amino-6-trifluoromethyl-benzoyl)-piperidin-4-yl]-5-butyl-3-593.6 cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3475-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-4-nitro-benzoyl)-piperidin-4-583.6 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-onetrifluoro-acetic acid;I-3484-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-4-methyl-piperidin-4-538 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; I-3494-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-azetidin-3-yl]-1-oxa-496 3,8-diaza-spiro[4.5]decan-2-one; compound with trifluoro-acetic acidI-3504-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-pyrrolidin-3-yl]-1-510 oxa-3,8-diaza-spiro[4.5]decan-2-one I-3514-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-4-isobutyl-piperidin-580 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-3524-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-4-ethyl-piperidin-4-552 yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-3535-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-540 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-3545-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-540 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith methanesulfonic acid I-3555-Butyl-3-(4,4-difluoro-cyclohexylmethyl)-9-[1-(2,6-dimethyl-benzoyl)-574 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-3565-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-4-methyl-piperidin-4-552 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with3,3,3-trifluoro- propionic acid I-3575-Butyl-3-cyclohexylmethyl-9-[4-methyl-1-(2,4,5-trimethyl-thiophene-3-572 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3585-Butyl-3-cyclohexylmethyl-9-[1-(2-dimethylamino-benzoyl)-4-methyl- 567piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3595-Butyl-9-[1-(2-chloro-6-fluoro-benzoyl)-4-methyl-piperidin-4-yl]-3- 577cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3605-Butyl-3-cyclohexylmethyl-9-[1-(3,5-dimethyl-isoxazole-4-carbonyl)-4-543 methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3619-[1-(Benzofuran-4-carbonyl)-4-methyl-piperidin-4-yl]-5-butyl-3- 564cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3625-Butyl-3-cyclohexylmethyl-9-[1-(2-fluoro-6-methoxy-benzoyl)-4-methyl-572 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3635-Butyl-3-cyclohexylmethyl-9-[1-(3,5-dimethyl-1-phenyl-1H-pyrazole-4-618carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3645-Butyl-3-cyclohexylmethyl-9-[1-(3,5-dimethyl-1H-pyrazole-4-carbonyl)-4-542 methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3655-Butyl-3-cyclohexylmethyl-9-[1-(2,4-dimethyl-pyridine-3-carbonyl)-4-methyl-553 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3665-Butyl-3-cyclohexylmethyl-9-[4-methyl-1-(thiophene-3-carbonyl)-piperidin-4-530 yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3675-Butyl-3-cyclohexylmethyl-9-[1-(4-methoxy-thiophene-3-carbonyl)-4-methyl-560 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3685-Butyl-3-cyclohexylmethyl-9-[1-(furan-3-carbonyl)-4-methyl-piperidin-4-yl]-514 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3699-[1-(5-Bromo-furan-3-carbonyl)-4-methyl-piperidin-4-yl]-5-butyl-3- 593cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3705-Butyl-3-cyclohexylmethyl-9-[1-(2-methoxy-4,6-dimethyl-pyrimidine-5-584carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3715-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-2-phenyl-pyrimidine-5- 630carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3725-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-2-pyridin-4-yl-pyrimidine-5-631carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3733-Cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-5-phenyl-1-558 oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3745-Butyl-3-cyclohexylmethyl-9-[1-(2,5-dimethyl-furan-3-carbonyl)-4-methyl-542 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3755-Butyl-3-cyclohexylmethyl-9-[4-methyl-1-(2-methyl-furan-3-carbonyl)-528 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3765-Butyl-3-cyclohexylmethyl-9-{1-[5-(4-methoxy-phenyl)-2-methyl-furan-3-634carbonyl]-4-methyl-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3775-Butyl-3-cyclohexylmethyl-9-{1-[3-(4-methoxy-phenyl)-5-methyl-isoxazole-6354-carbonyl]-4-methyl-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3785-Butyl-3-cyclohexylmethyl-9-{1-[1-(4-fluoro-phenyl)-3,5-dimethyl-1H-636 pyrazole-4-carbonyl]-4-methyl-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-379N-{3-[4-(5-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,9-diaza-spiro[5.5]undec-587 9-yl)-4-methyl-piperidine-1-carbonyl]-thiophen-2-yl}-acetamide;compound with trifluoro-acetic acid I-3805-Butyl-9-{1-[5-(4-chloro-phenyl)-2-methyl-furan-3-carbonyl]-4-methyl-639piperidin-4-yl}-3-cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3815-Butyl-3-cyclohexylmethyl-9-{1-[1-(3,4-dichloro-phenyl)-3,5-dimethyl-1H-687 pyrazole-4-carbonyl]-4-methyl-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-3825-Butyl-3-cyclohexylmethyl-9-{1-[1-(3,4-dichloro-phenyl)-3,5-dimethyl-1H-687 pyrazole-4-carbonyl]-4-methyl-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-3835-Butyl-9-[1-(5-chloro-4-ethyl-thiophene-3-carbonyl)-4-methyl-piperidin-4-yl]-593 3-cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3845-Butyl-3-cyclohexylmethyl-9-{1-[4,6-dimethyl-2-(2-methyl-thiazol-4-yl)-651 pyrimidine-5-carbonyl]-4-methyl-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-3855-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-2-trifluoromethyl-pyrimidine-6225-carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3865-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-2-methylsulfanyl-pyrimidine-5605-carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3875-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dichloro-4-methyl-benzoyl)-4-methyl-607 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3889-[1-(2-Bromo-6-methyl-benzoyl)-4-methyl-piperidin-4-yl]-5-butyl-3- 617cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound withtrifluoro-acetic acid I-3895-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dichloro-4-methanesulfonyl-benzoyl)-4-671 methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3905-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-554 methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3913-Cyclohexylmethyl-8-[1-(4-methoxy-2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-512 methyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one I-3925-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-540 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith methanesulfonic acid I-3935-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-piperidin-4-yl]-3- 542(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3945-Butyl-3-cyclohexylmethyl-9-[1-(2,4,6-trimethyl-pyrimidine-5-carbonyl)-554.7 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-3955-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-2-trifluoromethyl-pyrimidine-608.55-carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-oneI-3965-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-2-methylsulfanyl-pyrimidine-586.55-carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-3975-Butyl-9-[1-(4,6-dimethyl-2-methylsulfanyl-pyrimidine-5-carbonyl)-piperidin-588.54-yl]-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-3985-Butyl-3-cyclohexylmethyl-9-[1-(2-methanesulfinyl-4,6-dimethyl-pyrimidine-602.55-carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-oneI-3995-Butyl-3-cyclohexylmethyl-9-{1-[4,6-dimethyl-2-(pyrimidin-2-ylsulfanyl)-650.6pyrimidine-5-carbonyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-4005-Butyl-3-cyclohexylmethyl-9-[1-(2-methanesulfinyl-4,6-dimethyl-pyrimidine-618.55-carbonyl)-piperidin-4-yl]-9-oxy-1-oxa-3,9-diaza-spiro[5.5]undecan-2-onetrifluoro-acetic acid; I-4015-Butyl-3-cyclohexylmethyl-9-{1-[4,6-dimethyl-2-(pyridin-2-yloxy)- 633.6pyrimidine-5-carbonyl]-piperidin-4-yl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-4025-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-2-phenoxy-pyrimidine-5-632.6 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-4035-Butyl-3-cyclohexylmethyl-9-{1-[4,6-dimethyl-2-(pyridin-2-ylsulfanyl)-649.6pyrimidine-5-carbonyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-4045-Butyl-3-cyclohexylmethyl-9-{1-[4,6-dimethyl-2-(1-methyl-1H-imidazol-2-652.6ylsulfanyl)-pyrimidine-5-carbonyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-4055-Butyl-3-cyclohexylmethyl-9-{1-[4,6-dimethyl-2-(pyridin-4-yloxy)- 633.6pyrimidine-5-carbonyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-4065-Butyl-3-cyclohexylmethyl-9-{1-[4,6-dimethyl-2-(2-methyl-imidazol-1-yl)-620.6pyrimidine-5-carbonyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-4075-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-2-pyridin-4-yl-pyrimidine-5-617.6 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-4085-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-2-phenyl-pyrimidine-5-616.7 carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-4095-Butyl-3-cyclohexylmethyl-9-(1-[4,6-dimethyl-2-(2-methyl-thiazol-4-yl)-637.7pyrimidine-5-carbonyl]-piperidin-4-yl}-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-4103′-[4-(5-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,9-diaza-spiro[5.5]undec-9-658.6 yl)-piperidine-1-carbonyl]-2′,4′-dimethyl-biphenyl-4-carboxylicacid; compound with trifluoro-acetic acid I-4119-[1-(2-Amino-4,6-dimethyl-pyrimidine-5-carbonyl)-piperidin-4-yl]-5-butyl-3-555.6 cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-4125-Butyl-3-cyclohexylmethyl-9-[1-(2,4-dimethyl-biphenyl-3-carbonyl)-614.6 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-4135-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-3-pyridin-4-yl-benzoyl)-615.6 piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-4145-Butyl-9-[1-(4,6-dimethyl-2-trifluoromethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-4155-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-4165-Butyl-3-(4,4-difluoro-cyclohexylmethyl)-9-[1-(4,6-dimethyl-2-trifluoromethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-4175-Butyl-3-(4,4-difluoro-cyclohexylmethyl)-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;compound with trifluoro-acetic acid I-4185-Butyl-9-{1-[1-(4-fluoro-phenyl)-3,5-dimethyl-1H-pyrazole-4-carbonyl]-4-methyl-piperidin-4-yl}-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-4195-Butyl-9-{1-[3-(4-methoxy-phenyl)-5-methyl-isoxazole-4-carbonyl]-4-methyl-piperidin-4-yl}-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compound with trifluoro-acetic acid I-420(S)-5-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-421(R)-5-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one I-4225-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; compoundwith trifluoro-acetic acid I-423

662 I-4244-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-((S)-3-hydroxy-2-500.9 methyl-propyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one; compoundwith trifluoro-acetic acid

Compound Preparation

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Efforts have been made to ensure accuracy with respect to numbers used(e.g., amounts, temperatures), but allowance for some experimental errorand deviation, including differences in calibration, rounding ofnumbers, and the like, is contemplated.

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below. The starting materials and reagents used in preparingthese compounds generally are either available from commercialsuppliers, such as Aldrich Chemical Co., or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis;Wiley & Sons: New York, Volumes 1-21; R. C. LaRock, ComprehensiveOrganic Transformations, 2^(nd) edition Wiley-VCH, New York 1999;Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R.Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1984, vol. 1-9;Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees(Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley &Sons: New York, 1991, Volumes 1-40. The following synthetic reactionschemes are merely illustrative of some methods by which the compoundsof the present invention can be synthesized, and various modificationsto these synthetic reaction schemes can be made and will be suggested toone skilled in the art having referred to the disclosure contained inthis Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data. Unless specified to the contrary, the reactions describedherein preferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

Some compounds in following schemes are depicted with generalizedsubstituents; however, one skilled in the art will immediatelyappreciate that the nature of the R groups can varied to afford thevarious compounds contemplated in this invention. Moreover, the reactionconditions are exemplary and alternative conditions are well known. Thereaction sequences in the following examples are not meant to limit thescope of the invention as set forth in the claims.

The 1-oxa-3,8-diaza-spiro[4.5]decan-2-one ring system can be assembledfrom an N-protected 4-oxo-piperidine derivative. The parent 4-piperidoneis commercially available or, alternatively, it can be prepared bycyclization of 3-(2-ethoxycarbonyl-ethylamino)-propionic acid ethylester (L. Ruzicka et al., Helv. Chim, Acta 1920 3:812). While Scheme 1is depicted with the benzyloxycarbonyl protecting group 1a (Z=CO₂CH₂Ph),which is readily introduced by standard protocols utilizingbenzyloxycarbonyl chloride, one will appreciated that a variety of otherwell-known nitrogen protecting groups would also suffice (T. W. Greeneand P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley & Sons,New York 1999). Construction of the oxazolidinone ring follows thegeneral outline of the route reported by P. W. Smith et al. (J. Med.Chem. 1995 38:3772) and J. M. Caroon et al. (J. Med. Chem. 198224:1320).

The dianion of butyric acid was treated with4-oxo-piperidine-1-carboxylic acid benzyl ester to afford the tertiarycarbinol 11a. Carboxylic acid dianions (J. C. Stowell, Carbanions inOrganic Synthesis, Wiley-Interscience, New York, 1979, pp. 127-216; N.Petragnani et al. Synthesis 1982 521) are prepared by treating thecarboxylic acid with two equivalents of base. While the reaction isconveniently carried out with lithium diisopropylamide, a variety ofother non-nucleophilic strong bases, e.g. lithium2,2′,6,6′-tetramethylpiperidide or lithium hexamethyldisilazane can alsobe used. The base and carboxylic acid are typically combined at −78° C.and the initially formed carboxylate salt warmed to 0 to 20° C. toproduce the dianion quantitatively. The reaction is run in polar inertsolvents and THF, dioxane, dimethoxyethane are commonly used. Byutilizing different carboxylic acids the substituent at the 4-positionof the oxazolidone can easily be varied.

A variation of the Curtius reaction is employed to introduce thenitrogen atom and concomitantly generate a reactive acyl species whichtraps the hydroxyl; group and completes the spiro ring formation. Thecharacteristic feature of the Curtius-type rearrangement of acyl azidesis the loss of nitrogen and formation of a positively charged “nitroniumion” which undergoes 1,2-alkyl shift and produces an isocyanate whichtraps the alcohol. Diphenoxyphosphoryl azide (DPPA) has proven to be aconvenient reagent to form the acyl azide in situ. Variations that canbe used to convert a carboxylic acid derivative to the correspondingamine include the Hofmann, Schmidt or Lossen reactions (J. MarchAdvanced Organic Chemistry 4^(th) Ed J Wiley & Sons: New York, 1991; pp1090-1095; T. Shioiri Degradation Reactions in Comprehensive OrganicSynthesis, vol. 6, E. Winterfeldt (Ed) Pergamon, Oxford 1991 p.795-825).

Alkylation of an amide is accomplished by treating the amine or a metalsalt of the amine (i.e. a deprotonated form) with a compound RZ¹ whereinZ¹ is a leaving group such as halo, C₁₋₄ alkanesulphonyloxy,benzenesulphonyloxy or p-toluenesulphonyloxy, optionally in the presenceof a base and/or a phase transfer catalyst. The reaction may typicallybe carried out in the presence of a base such as triethylamine orN,N-diisopropylethylamine; DBU (1,8-diazabicyclo[5,4,0]undec-7-ene; oran inorganic base such as Na₂CO₃, NaHCO₃, K₂CO₃ or Cs₂CO₃, optionally inthe presence of a phase transfer catalyst, and in a solvent such asacetonitrile, DMF, DMSO, 1,4-dioxane, THF or toluene. A metal salt canbe formed by treating the amide with a base such as sodium or potassiumhydride, lithium diisopropyl amide, potassium tert-butoxide or sodiumamylate in a non-protonated solvent such as THF, DMF or 1,4-dioxanewhich is then treated with a compound RZ¹. Introduction of a substituentonto the urethane nitrogen was accomplished by N-alkylation of thesodium salt of the amine which was generated by treating 12 with sodiumhydride and subsequently treating the salt with an alkyl halide toafford 13.

Removal of the carbobenzyloxy protecting group is carried out catalytichydrogenation. The deprotection conditions will, of course, vary withthe nature of the N-protecting group. Acidic conditions also can be usedto remove a benzyloxycarbonyl protecting group. The tert-butoxycarbonylis a convenient alternative to the benzyloxycarbonyl protecting groupwhich is removed in treatment with trifluoroacetic acid. One skilled inthe art will recognize alternative protecting groups can usedinterchangeably which may alter the deprotection conditions.

The incorporation of the second piperidine ring is carried out byreductive amination of an N-acyl 4-piperidone. A reductive amination ispreferably carried out by combining an amine and carbonyl compound inthe presence of a complex metal hydride such as sodium borohydride,lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodiumtriacetoxyborohydride or borane/pyridine conveniently at a pH of 1-7optionally in the presence of a dehydrating agent such as molecularsieve or Ti(IV)(O-i-Pr)₄ to facilitate formation of the intermediateimine and at ambient temperature or with hydrogen in the presence of ahydrogenation catalyst, e.g. in the presence of palladium/charcoal, at ahydrogen pressure of 1 to 5 bar, preferably at temperatures between 20°C. and the boiling temperature of the solvent used. It may also beadvantageous during the reaction if reactive groups are protected duringthe reaction by conventional protecting groups which are cleaved againby conventional methods after the reaction. Reductive aminationprocedures have been reviewed: R. M. Hutchings and M. K. HutchingsReduction of C═N to CHNH by Metal Hydrides in Comprehensive OrganicSynthesis col. 8, I. Fleming (Ed) Pergamon, Oxford 1991 pp. 47-54.

To prepare compound libraries, the availability of an advancedintermediate which can be reacted with a variety of fragments is oftenadvantageous. Thus an alternate scheme (Scheme 2) is comprised ofcarrying out the reductive alkylation of 14 with 10 (R=CBZ or Boc)Reductive amination and subsequent deprotection of the piperidinenitrogen affords 17. Acylation of the free amine with2,6-dimethylbenzoic acid affords 16; however, it should be readilyapparent that 17 can be acylated or alkylated with a variety ofcompounds to afford a chemical library with diverse functionality on thepiperidine which may be used in lead identification and optimizationprograms.

Amides of 17 may be formed by conventional amide bond formationtechniques such as by first activating a carboxylic acid either as anacid chloride or acid anhydride. The activated acid and the amine 17 maybe reacted in the presence of an excess of a suitable base, e.g.,Na₂CO₃, NaHCO₃, K₂CO₃, triethylamine or N,N-diisopropylethylamine, andin a suitable solvent, e.g. dichloromethane, ethyl acetate, THF ortoluene, with or without water as a co-solvent Alternatively an esterand an amine, or a metal salt thereof, may reacted together in thepresence of a base, e.g. triethylamine, and an optional catalyst in asolvent such as dichloromethane, ethyl acetate, THF or toluene. In yetanother alternative the acid may be activated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI),1,1′-carbonyldiimidazole (CDI) or 1,3-dicyclohexylcarbodiimide (DCC) and1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole hydrate(HOBT), and reacted with the amine in the presence of a base, e.g.triethylamine, in a solvent such as THF, dichloromethane or toluene. Oneskilled in the art will appreciate there are many alternatives to thereagents identified above which activate a carboxylic acid in likemanner. These reactions are typically run at a moderately reducedtemperature between about −10 to +10° C. and are typically complete inseveral hours. The product is recovered by conventional means.

The secondary amine 17 can also be converted to sulfonamides (17a;R=SO₂Z¹ wherein Z¹ is alkyl or aryl) by treating 17 with aryl sulfonylchlorides under Schotten-Bauman conditions. Ureas and thioureas (17a:R=CONR′R″ or CSNHR′R″) are also accessible from 17. Procedures forpreparing ureas and thioureas have been described (J. Barluenga et al.Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms Otherthan Halogen or a Chalcogen, in Comprehensive Organic Functional GroupTransformations, vol. 6, Thomas L. Gilchrist (ed) Elsevier Science Ltd.,Oxford UK). Alkyl or aryl isothiocyanates react with ammonia, primaryand secondary amines to give 1-substituted, 1,3-disubstituted andtrisubstituted thioureas respectively. This reaction generally takesplace with good yields and polar solvents such as diethyl ether,ethanol, water and acetone are usually preferred. Alternatively an aminecan be treated with phosgene or a phosgene equivalent (e.g. carbonyldiimidazole) and afford an aminocarbonyl chloride which is treated withammonia, primary or secondary amines. Thioureas are prepared byanalogous procedures utilizing isothiocyanates or thiophosgene anequivalent thereof.

Introduction of a methyl radical at the 4-position was accomplished bytreating the intermediate amino nitrile 18 from the Ti(O-i-Pr)₄catalyzed condensation of 14 and N—BOC-4-oxopiperidine withdiethylaluminum cyanide and subsequently displacing the nitrile withmethyl magnesium bromide to afford 19 (A. Palani et al. J. Med. Chem.2001 44(21):3339-42).

4-Alkylidenyl (23: R′=alkyl), 4-aralkylidenyl (23: R′=aralkyl),4-heteroarylalkylidenyl (23: R′=heteroarylalkyl) and4-heterocycloalkylidenyl (23: R′=heterocyclylalkyl) compounds can beprepared by exploiting the susceptibility of acetylenes to nucleophilicattack by nitrogen nucleophiles to afford 4-alkylidene compounds 23 (M.Kimura et al., Tetrahedron Lett. 1990 31(30):4887-4890; N. Shachat andJ. J. Bagnell, Jr., J. Org. Chem. 1963 28:991; S. J. Miller and R.Tanaka, Nucleophilic Additions to Acetylenes in Selective OrganicTransformations, vol. 1, B. S. Thyagarajan (ed.) Wiley & Sons, New York,N.Y., 1970, p. 143) as depicted in Scheme 4.

Propargyl carbinols 21 are prepared by addition of acetylide anions toN-benzyl-4-piperidone. Acetylide anions are prepared by treating aterminal acetylene with a strong base. Typical strong bases includealkyl lithiums, lithium dialkylamides, lithium hexamethyldisilazane, andsodium hydride. The reaction is run in a polar aprotic solvent such asTHF, DME or dioxane at temperatures ranging from −70 to 0° C. Thecyclization can be carried out by treating the resulting propargylcarbamate with sodium alkoxide in alcohol solvents to afford 23.Alternatively cyclization can be induced with copper(I) chloride andtriethylamine in refluxing THF.

The resulting exocyclic olefins 23 (R=CH₂Ph) are relatively resistant tohydrogenation under mild conditions allowing selective removal of thebenzyl protecting group to afford 23 (R=H) which can be converted tocompounds of formula 26 by reductive amination as previously describedin Schemes 1 and 2. High pressure hydrogenolysis (1000 psi) reduced theexo-olefin while also removing the benzyl protecting group to afford 24which was converted to piperidines 25 as described previously.

Acylation and alkylation of nitrites is accomplished by deprotonating anitrile with strong base to form the corresponding nitrile stabilizedcarbanions. Bases useful for forming a-α-cyano carbanions includelithium dialkyl amides, sodium hexamethyldisilazane, sodium or potassiumhydride or potassium amide The reactions are carried out in polaraprotic solvents such as THF, DME and dioxane. The reaction is run from−20 to −78° C. Addition of the N-benzyl piperidin-4-one 10 (R=CH₂Ph)compound to the carbanion derived from pentane nitrile afforded hydroxynitrile 27. (J. March, Adv. Organic Chemistry, John Wiley & Sons, NewYork, 1992, p. 468-474; S. Arseniyadis et al. Org Reactions 198431:1-364; H. O. House, Modern Synthetic Reactions, Benjamin Inc, MenloPark, Calif. 1972, p. 546-550).

Hydroxy nitrites can be convert amino alcohols with metal hydridereducing agents. (see, R. C. Larock, Comprehensive OrganicTransformations, Verlag Chemie, New York, N.Y. 1989, p. 993) Metalhydrides suitable for reduction of nitrites include diborane-THFcomplex, lithium aluminum hydride and diisobutylaluminum hydride.Diborane reductions are carried out in aprotic ethereal solvents,especially THF. Lithium aluminum hydride reductions can be carried outin THF or diethyl ether. DIBAL reductions are carried out in toluene orTHF. DIBAL is available as toluene solutions.

Intramolecular cyclization of the amino alcohol 30 with phosgene or aphosgene equivalent (e.g., carbonyl diimidazole) affords carbamate 29.The reaction is carried out in aprotic solvent in the presence oftrialkylamine base at temperatures ranging form 0-100° C.

The remainder of the synthesis of1-oxa-3,9-diaza-spiro[5.5]undecan-2-one compounds of the presentinvention, including N-alkylation, deprotection of the piperidinylnitrogen and reductive amination with a suitably N-derivatized4-oxopiperidine, is carried out utilizing processes analogous to thoseoutlined in Schemes 1 and 2 for 1-oxa-3,8-diaza-spiro[4.5]decan-2-ones.

Benzo-fused 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one compounds areprepared by treating metallated α-aminoalkoxycarbonyl aryl compound 10with a suitably N-protected 4-oxo-piperidine (Scheme 6). Theaminoalkoxycarbonyl radical directs metallation of the aryl ringregiospecifically adjacent to the heteroatom (for analogous orthometallation of aminoacyl aryl compounds see, H. Takai et al., Chem.Pharm. Bull. 1985 33(3):1129-39; W. Fuhrer and H. W. Geschwend, J. Org.Chem. 1979 44:113-36) to afford an intermediate alkoxycarbonylaminoalcohol compound which spontaneously cyclizes to afford4,4-disubstitituted 1,4-dihydro-benzo[d][1,3]oxazin-2-one 33. Theremainder of the synthesis of benzo-fused1-oxa-3,9-diaza-spiro[5.5]undecan-2-one compounds of the presentinvention, including N-alkylation, deprotection of the piperidinylnitrogen and reductive alkylation with a suitable N-derivatized4-oxopiperidine 10, is carried out utilizing processes analogous tothose outlined in Schemes 1 and 2 for1-oxa-3,8-diaza-spiro[4.5]decan-2-ones.

4-Butyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid benzylester (12) contains an asymmetric carbon and therefore is a mixture oftwo enantiomers. Separation of the diastereomers was accomplished byacylating 12 with (−)-camphanic acid and separating the resultingdiastereomers 38a and 38b that exhibit different physical properties andmay be separated by conventional means including silica gelchromatography, fractional crystallation and high pressure liquidchromatography (Scheme 7).

The individual diastereomers camphanic amides were hydrolyzed withlithium hydroxide to afford 39a and 39b which were carried on asdescribed previously.

The chiral synthesis of 1421 (SCHEME 8) was achieved utilizing anasymmetric hydroxylation of 55 which was prepared by Wittig olefinationof 10 (R=BOC) with pentylidene-triphenyl-μ⁵-phosphane. Asymmetricdihydroxylation is carried out with AD-mix-β which is well know in theart and consists of a premix containing of K₃Fe(CN)₆, K₂CO₃, K₂OsO₂(OH)₄and hydroquinidine 1,4-diphthalazinediyl diether. Asymmetrichydroxylation is well known in the art and for references see, H. C.Kolb et al. Chem. Rev. 1994 94:2483-2547, K. B. Sharpless et al. J. Org.Chem. 1992 57:2768-2771. The resulting asymmetric diol 56 wasselectively mesylated on the secondary alcohol and converted to epoxide57. Epoxide-opening mediated by Et₃AlCN afforded the hydroxynitrile 58awhich was reduced to amino alcohol 58b and cyclized with phosgene toyield 59a. Introduction of the cyclohexylmethyl substituents (step 6),removal of the Boc protecting group (step 7) and reductive aminationwith 15 (step 8) affording chiral I-421. While present evidence suggeststhe isomer obtained from this sequence is the (R) enantiomer, bothenantiomers have been prepared and both are with the scope of thepresent patent.

Dosage and Administration

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms and carriers. Oraladministration can be in the form of tablets, coated tablets, dragées,hard and soft gelatine capsules, solutions, emulsions, syrups, orsuspensions. Compounds of the present invention are efficacious whenadministered by other routes of administration including continuous(intravenous drip) topical parenteral, intramuscular, intravenous,subcutaneous, transdermal (which may include a penetration enhancementagent), buccal, nasal, inhalation and suppository administration, amongother routes of administration. The preferred manner of administrationis generally oral using a convenient daily dosing regimen which can beadjusted according to the degree of affliction and the patient'sresponse to the active ingredient.

A compound or compounds of the present invention, as well as theirpharmaceutically useable salts, together with one or more conventionalexcipients, carriers, or diluents, may be placed into the form ofpharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. A typical preparation will contain from about 5% toabout 95% active compound or compounds (w/w). The term “preparation” or“dosage form” is intended to include both solid and liquid formulationsof the active compound and one skilled in the art will appreciate thatan active ingredient can exist in different preparations depending onthe target organ or tissue and on the desired dose and pharmacokineticparameters.

The term “excipient” as used herein refers to a compound that is usefulin preparing a pharmaceutical composition, generally safe, non-toxic andneither biologically nor otherwise undesirable, and includes excipientsthat are acceptable for veterinary use as well as human pharmaceuticaluse. The term “excipient” as used herein includes both one and more thanone such excipient.

Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier may beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material. In powders,the carrier generally is a finely divided solid which is a mixture withthe finely divided active component. In tablets, the active componentgenerally is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers include but are not limited to magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Solid form preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Liquid formulations also are suitable for oral administration includeliquid formulation including emulsions, syrups, elixirs, aqueoussolutions, aqueous suspensions. These include solid form preparationswhich are intended to be converted to liquid form preparations shortlybefore use. Emulsions may be prepared in solutions, for example, inaqueous propylene glycol solutions or may contain emulsifying agentssuch as lecithin, sorbitan monooleate, or acacia. Aqueous solutions canbe prepared by dissolving the active component in water and addingsuitable colorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into to the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polyactic acid.

Suitable formulations along with pharmaceutical carriers, diluents andexpcipients are described in Remington: The Science and Practice ofpharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19thedition, Easton, Pa. A skilled formulation scientist may modify theformulations within the teachings of the specification to providenumerous formulations for a particular route of administration withoutrendering the compositions of the present invention unstable orcompromising their therapeutic activity.

The modification of the present compounds to render them more soluble inwater or other vehicle, for example, may be easily accomplished by minormodifications (salt formulation, esterification, etc.), which are wellwithin the ordinary skill in the art. It is also well within theordinary skill of the art to modify the route of administration anddosage regimen of a particular compound in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectin patients.

The term “therapeutically effective amount” as used herein means anamount required to reduce symptoms of the disease in an individual. Thedose will be adjusted to the individual requirements in each particularcase. That dosage can vary within wide limits depending upon numerousfactors such as the severity of the disease to be treated, the age andgeneral health condition of the patient, other medicaments with whichthe patient is being treated, the route and form of administration andthe preferences and experience of the medical practitioner involved. Fororal administration, a daily dosage of between about 0.01 and about 100mg/kg body weight per day should be appropriate in monotherapy and/or incombination therapy. A preferred daily dosage is between about 0.1 andabout 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg bodyweight and most preferred 1.0 and about 10 mg/kg body weight per day.Thus, for administration to a 70 kg person, the dosage range would beabout 7 mg to 0.7 g per day. The daily dosage can be administered as asingle dosage or in divided dosages, typically between 1 and 5 dosagesper day. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect for theindividual patient is reached. One of ordinary skill in treatingdiseases described herein will be able, without undue experimentationand in reliance on personal knowledge, experience and the disclosures ofthis application, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease and patient.

In embodiments of the invention, the active compound or a salt can beadministered in combination with another antiviral agent, such as anucleoside reverse transcriptase inhibitor, another nonnucleosidereverse transcriptase inhibitor or HIV protease inhibitor. When theactive compound or its derivative or salt are administered incombination with another antiviral agent the activity may be increasedover the parent compound. When the treatment is combination therapy,such administration may be concurrent or sequential with respect to thatof the nucleoside derivatives. “Concurrent administration” as usedherein thus includes administration of the agents at the same time or atdifferent times. Administration of two or more agents at the same timecan be achieved by a single formulation containing two or more activeingredients or by substantially simultaneous administration of two ormore dosage forms with a single active agent.

It will be understood that references herein to treatment extend toprophylaxis as well as to the treatment of existing conditions, and thatthe treatment of animals includes the treatment of humans as well asother animals. Furthermore, treatment of a HIV infection, as usedherein, also includes treatment or prophylaxis of a disease or acondition associated with or mediated by HIV infection, or the clinicalsymptoms thereof.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

EXAMPLE 14-Butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one(I-1)

Step 1: 4-(1-Carboxy-pentyl)-4-hydroxy-piperidine-1-carboxylic acidbenzyl ester

To a solution of 15 mL (124 mmol) diisopropyl amine in 90 mL anhydrousTHF at −40° C. was added dropwise 45 mL (113 mmol) of n-butyl lithium(2.5 M in hexanes) The reaction mixture was warmed to 0° C. A solutionof 6.7 mL (62.1 mmol) hexanoic acid in 60 mL anhydrous THF was addeddropwise. The reaction mixture stirred at −20° C. for an additional 20m. The reaction mixture was cooled to −78° C. A solution of 15 g (64.3mmol) benzyl 4-oxo-1-piperidine-carboxylate in 60 mL anhydrous THF wasadded dropwise. The reaction mixture slowly warmed to room temperatureover 18 h. The reaction was quenched by addition of 25 mL of water. Themixture was acidified to pH 2 with 6N HCl. The aqueous layer was thriceextracted with EtOAc. The combined organic phase was dried overmagnesium sulfate and evaporated under reduced pressure. Toluene wasadded to the light, yellow oil and evaporated under reduced pressure toprovide 21.5 g (99%) of4-(1-carboxy-pentyl)-4-hydroxy-piperidine-1-carboxylic acid benzylester: ms [M]⁺=350.

Step 2: 4-butyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acidbenzyl ester

To a solution of 27 g of4-(1-carboxy-pentyl)-4-hydroxy-piperidine-1-carboxylic acid benzyl ester(61.5 mmol) in 500 ml toluene was added sequentially 20.4 mL of TEA(68.5 mmol) and 14.8 mL of diphenyl phosphoryl azide (68.5 mmol) Thereaction mixture refluxed under a nitrogen atmosphere for 18 hour.

The reaction mixture was cooled to room temperature and evaporated underreduced pressure. The residue was dissolved in ethyl acetate. Themixture was washed twice with 1 N HCl, twice with saturated sodiumbicarbonate, and once with brine. The organic phase was dried overmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by flash chromatography on silica gel (1:5 EtOAc:DCM) toprovide 16.2 g (75%) of4-butyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid benzylester: ms [M]⁺=347.

Step 3:4-butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicacid benzyl ester

To a solution of 5.0 g4-butyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid benzylester (14.4 mmol) in 50 mL DMF was added 994 mg of sodium hydride (21.6mmol, 60% dispersion in mineral oil). The reaction mixture stirred forfive minutes and 2.2 mL of cyclohexylmethyl bromide (15.8 mmol) was thenadded. The reaction mixture stirred under nitrogen for 18 h. Thereaction mixture was heated to 70° C. for three h. The reaction mixturecooled to room temperature and was diluted with 500 mL EtOAc and washedtwice with water, once with brine. The organics were dried overmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by flash chromatography on silica gel utilizing a gradientelution (10% to 15% EtOAc/DCM) to provide 4.1 g (65%) of4-butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylicacid benzyl ester: ms [M]⁺=443.

Step 4:4-butyl-3-cyclohexylmethyl-1-oxa-3,8-diaza-spiro[4.5]decane-2-one

Palladium on activated carbon (10 mol %; 10% by weight, dry basis,Degussa type) was suspended in a solution of 2.07 g (4.7 mmol) of the4-butyl-3-cyclohexylmethyl-2-α-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylicacid benzyl ester and 50 mL EtOH. The reaction mixture stirred under ahydrogen atmosphere for 18 h. The solution was filtered through a pad ofCELITE® to remove the catalyst. Evaporation the EtOH under reducedpressure afforded 1.4 g (95%) of4-butyl-3-cyclohexylmethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one: ms[M]⁺=309.

Step 5:4-butyl-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one

To a solution of 0.75 g (2.4 mmol) of 14 (R=n-Bu; R=c-C₅H₁₁) and 0.59 g(2.55 mmol) of 15 in 30 mL of dichloroethane was added 1.0 mL (3.4 mmol)of titanium (IV) isopropoxide. The reaction mixture was stirred at RT.After 16 h added 0.77 g (3.85 mmol) of sodium triacetoxyborohydride wasadded and stirred continued at RT. After 4 h added CELITE® and 15 mL 2NNaOH were added. The mixture was stirred at RT. After 0.5 h, the CELITE®was filtered and washed with dichloromethane and the organic layerseparated. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. The residue was purified by flashchromatography and eluted with a gradient (50% ethyl acetate/hexane,ethyl acetate, 5% methyl alcohol/ethyl acetate/0.4% ammonium hydroxide)to afford 0.7 g (56%) of I-1 as a white foam.

EXAMPLE 24-(4-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-4-methyl-piperidine-1-carboxylicacid (2,6-dimethyl-phenyl)-amide (I-80)

Step 1:4-(4-Butyl)-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4,5]dec-8-yl)-4-cyano-piperidine-1-carboxylicacid tert-butyl ester (18: R=Boc; R′=n-Bu; R″=c-C₅H₁₁)

To a solution of 14 (R′=n-Bu; R″=c-C₅H₁₁; 2.46 mmol) in 60 mL ofdichloromethane was added N-Boc-4-piperidone, (10: R=Boc; 515 mg: 2.58mmol) at RT. The stirred reaction was maintained under a nitrogenatmosphere for 30 m. Ti(IV)(O-i-Pr)₄ (1 mL; 3.44 mmol) was added to thereaction and the mixture was stirred at RT for 12 h and then refluxedfor 4 h. The reaction mixture was cooled to room temperature anddiethylaluminum-cyanide (3.8 mL; 3.87 mmol) was added and stirring wascontinued for another 5 days. The reaction mixture was diluted with 50mL of dichloromethane and a few drops of 1N NaOH were added untilaluminum granulates could be removed by filtration through CELITE® Theorganic layer was removed in vacuo and the residue purified on flashchromatography, on silica gel (50% EtOAc/hexane to afford the titlecompound (933 mg; 78% theory).

Step 2:4-(4-butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-4-methyl-piperidine-1-carboxylixacid tert-butyl ester (19: R=Boc; R′=n-Bu; R″=c-C₅H₁₁)

To a solution of4-(4-butyl-(3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-4-cyano-piperidine-1-carboxylicacid tert-butyl ester (18: R=Boc; R′=n-Bu; R″=c-C₅H₁₁; 700 mg; 1.35mmol) in 25 mL of THF under nitrogen atmosphere was added withmethyl-magnesium-bromide, (1.3 mL; 4.06 mmol; 3.0M solution in Et₂O) atRT. The reaction mixture was stirred for 24 h. The reaction was quenchedby the addition of water and EtOAc (1:1; 100 mL) and filtered throughCELITE®. The organic phase was separated and dried with sodium sulfate,filtered and the solvent evaporated to afford 545 mg (79%) of 19 (R=Boc;R′=n-Bu; R″=c-C₅H₁₁): ms [M]⁺=506.

Step 3:4-butyl-3-cyclohexyl-methyl-8-(4-methyl-piperidin-4-yl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one19b (R=n-Bu; R″=c-C₅H₁₁)

To a solution of4-(4-butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-4-methyl-piperidine-1-carboxylicacid tert-butyl ester (19a: R=n-Bu; R″=c-C₅H₁₁; 545 mg; 1.07 mmol) in 20mL of dichloromethane was added 1 mL of TFA at room temperature andrefluxed for 3 h., then stirred for 24 h. at room temperature. Thedichloromethane solution was washed with 1N NaOH and water (2×50 ml) andbrine (50 ml). The organic layer was separated and dried with sodiumsulfate, filtered and the solvent evaporated to afford 300 mg (80%theory) of 19b (R=n-Bu; R″=c-C₅H₁₁); ms [M]⁺=406.

Step 4:4-(4-Butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl)-4-methyl-piperidine-1-carboxylicacid (2,6-dimethyl-phenyl)-amide (I-80)

A mixture of 2,6-dimethylbenzoic acid (333 mg, 1.47 mmol), HOBT (225 mg,1.66 mmol) and PS-carbodiimide (610 mg, 196 mmol) in 20 mL of 10%DMF/dichloromethane) was stirred at RT. After 16 h, a solution of 19b(400 mg, 0.98 mmol; R=n-Bu; R″=c-C₅H₁₁) in 20 mL of DCM was added. Thereaction mixture was stirred at RT for 48 h. The resulting mixture wasfiltered through CELITE® and washed with 110% DMF/DCM. The filtrate wasevaporated to dryness under reduced pressure and the crude product waspurified by flash chromatography on silica gel (25% MeOH/EtOAc) and theresulting amine converted to the corresponding hydrochloride acid saltwith HCl/Et₂O to afford 1-80 (34.5 mg; 6% theory); ms [M+H]⁺=538.

EXAMPLE 38-(1-Benzenesulfonyl-piperidin-4-yl)-4-butyl-3-cyclohexylmethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one(I-71)

To a solution of 19b (R=n-Bu; R″=c-C₅H₁₁; 1.0 g; 2.24 mmol), TEA (0.311mL; 0.226 g; 2.24 mmol) and 25 mL of Et₂O was added 1.79 g oftoluenesulfonyl chloride (9.78 mmol). The reaction mixture was stirredat RT for 18 h. The solid triethylammonium chloride was filtered and thevolatile solvents were evaporated in vacuo. The residue was partitionedbetween EtOAc and 1N NaOH. The organic layer was washed with water andbrine, dried over magnesium sulfate, and evaporated to afford I-71. Thecrude product was purified by flash chromatography on silica gel.

EXAMPLE 44-Butylidene-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one(I-14)

Step 1:1-Benzyl-4-pent-1-ynyl-piperidin-4-ol

To a solution of 5.47 g (80.3 mmol) of 1-pentyne in 65 mL THF at −78° C.was added 32.1 ml n-butyl lithium (80.3 mmol; 2.5M in hexanes). Afterthe addition was complete the reaction mixture was warmed to 0° C. and asolution of 8.44 g (44.6 mmol) of 1-benzyl-4-piperidone and 40 mL of THFwas added dropwise. The cooling bath was removed and the reactionmixture was stirred at ambient temperature. After 17 h, the reaction wasquenched by addition of saturated ammonium chloride and diluted withEtOAc. The aqueous phase was extracted twice with EtOAc. The combinedorganic phases were washed with brine, dried over sodium sulfate andevaporated to afford a reddish-gold oil. The crude product was purifiedby flash chromatography on silica gel (EtOAc/hexane 1:1→65:35). Thelight gold oil was dried over sodium sulfate to afford 8.91 g (78%) of1-benzyl-4-pentynyl-4-piperidinol: ms (ESI) [M+H]⁺=258.

Step 2:8-Benzyl-4-butylidene-3-cyclohexylmethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one

To a solution of 21 (R=Bn; R′=n-Pr; 1.43 g (5.56 mmol) in 25 mL toluenewas added 9.8 mL of potassium t-amylate (16.68 mmol; 1.7 M in toluene).The mixture was heated to 50° C. and a solution of 851 mg (6.11 mmol) ofcyclohexylmethylisocyanate (J. Med. Chem. 1996 39:1157-1163) in 6 mLtoluene was added. The reaction was heated at 70° C. for 17 h, quenchedwith saturated ammonium chloride and diluted with ethyl acetate. Theaqueous phase was washed twice with EtOAc and the combined organicphases washed with brine, dried over sodium sulfate and evaporated toafford a yellow oil. The crude product was purified by flashchromatography on silica gel (EtOAc/hexane 25:75) to afford 190 mg (9%)of 23 (R=Bn; R′=n-Pr; R″=c-C₅H₁₁) as an unstable light yellow oil: ms(ESI) [M+H]⁺=397.

Step 3:4-butylidene-3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one(I-14)

Removal of the benzyl protecting group from 23 (R=Bn; R′=n-Pr;R″=c-C₅H₁₁) was accomplished by catalytic hydrogenolysis in the presenceof 20% Pd(OH)₂/C and EtOH at about 40 psi. The final step was carriedout as described in step 5 of Example 1. The title compound (I-14) wasobtained as a clear glass (3%): MS (ESI) m/z [M+H]⁺ 522.

EXAMPLE 53-Cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-(2-methoxy-ethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one(I-12)

Step 1:1-Benzyl-4-(3-methoxy-prop-1-ynyl)-piperidin-4-ol

To a solution of 4.67 g (66.6 mmol) of 3-methoxypropyne in 50 mL THF at−78° C. was added 26.7 mL n-butyl lithium (66.6 mmol; 2.5M in hexanes).After the addition was complete the reaction mixture was warmed to 0° C.and a solution of 7.01 g (37.0 mmol) of 1-benzyl-4-piperidone and 35 mLTHF was added dropwise. The cooling bath was removed and the reactionmixture was stirred at ambient temperature. After 18 h, the reaction wasquenched with saturated ammonium chloride and diluted with water andEtOAc. The aqueous phase was washed with EtOAc and the combined organicphases washed sequentially with water and brine. The EtOAc was driedover sodium sulfate, filtered and evaporated in vacuo to afford areddish-gold oil. The crude product was purified by flash chromatographyon silica gel eluting with EtOAc/hexanes (8:2). The gold oil was driedto give 8.30 g (86%) of 21 (R=Bn; R′=CH₂OMe): ms (ESI) [M+H]⁺=260.

Step 2:8-Benzyl-3-cyclohexylmethyl-4-[2-methoxy-eth-(Z)-ylidene]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one

To a solution of 220 mg (0.85 mmol) of 21 (R=Bn; R′=CH₂OMe) dissolved in10 mL toluene was added 1.2 mL of potassium t-amylate (1.88 mmol; 1.7 Min toluene). The mixture was heated to 75° C. and a solution ofcyclohexylmethylisocyanate (22: R=c-C₅H₁₁; 186 mg; 1.88 mmol) in 3 mLtoluene was added. The reaction was heated at 75° C. for 17 h, quenchedwith water and diluted with ethyl acetate. The phases were separated andthe aqueous phase washed twice with EtOAc. The combined organic phaseswere washed with brine, dried over sodium sulfate, filtered andevaporated in vacuo to afford a gold oil. The crude product was purifiedby flash chromatography on silica gel and eluted with a gradient

EtOAc/hexanes (1:1→7:3) to afford 100 mg (29%) of 23 (R=Bn; R′=CH₂OMe;R″=c-C₅H₁₁) as a light yellow oil: ms (ESI) [M+H]⁺=399.

Step 3:3-Cyclohexylmethyl-4-(2-methoxy-ethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one

To a solution of 500 mg (1.25 mmol) of 21 (R=Bn; R′=CH₂OMe) in 15 mLEtOH was added 200 mg 20% Pd(OH)₂ on carbon and 5 drops of HClO₄. Themixture was pressurized to 1000 psi of H₂ in a steel reactor bomb andstirred at ambient temperature for 17 h. The reaction was filtered overCELITE® and the filter cake was washed with EtOH. The filtrate wasevaporated in vacuo and partitioned the residue between 1 M NaOH andEtOAc. The organic phase was washed sequentially with water and brine,dried over sodium sulfate and evaporated in vacuo to afford 268 mg (69%theory) of 24 (R′=CH₂OMe; R″=c-C₅H₁₁) as a yellow oil: ms (ESI)[M+H]⁺=311.

Step 4:3-Cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-(2-methoxy-ethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one

Reductive amination was carried out as described in step 5 of example 1.The crude product was purified by flash chromatography eluting with agradient of methylene chloride/ethanol (45:2→45:4) to afford 46 mg (10%theory) of 1-12 as a clear glass: ms (ESI) (M+H)⁺=526.

EXAMPLE 63-Cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-ethoxymethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one(I-11)

Step 1:8-benzyl-3-cyclohexylmethyl-4-methylene-1-oxa-3,8-diazaspiro[4.5]decan-2-one

The title compound was prepared in 57% yield using the proceduredescribed in step 2 of example 3 but substituting1-benzyl-4-ethynyl-piperidin-4-ol (21: R=Bn; R′=H; J. J. DeVoss, J. Med.Chem. 1994 37(5):665) for 1-benzyl-4-pent-1-ynyl-piperidin-4-ol. Thecrude product was purified by flash chromatography eluting withEtOAc/hexane (1:1) to afford 23 (R=Bn; R′=H; R″=c-C₅H₁₁) as a yellowsyrup: ms (ESI) [M+H]⁺=355.

Step 2:8-Benzyl-3-cyclohexylmethyl-4-hydroxymethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one

To a solution of 2.0 g (5.64 mmol) of 23 (R=Bn; R′=H; R″=c-C₅H₁₁) in 100mL of THF was added 2.75 g (11.28 mmol) of 9-BBN and the reaction wasrefluxed for 2 h. The reaction was cooled to 0° C. and 30 ml 1M NaOH wasadded followed by slow addition of 40 mL 30% H₂O₂. The mixture wasstirred at ambient temperature for 1.5 h, poured into a mixture of iceand water and quenched with 1M Na₂SO₃. The crude mixture was dilutedwith EtOAc and the aqueous phase was washed two times with EtOAc. Thecombined organic extracts were washed twice with 1M Na₂SO₃ then withwater and brine. The organic phase was dried over sodium sulfate,filtered and concentrated in vacuo to afford a yellow oil. The crudeproduct was purified by silica gel flash chromatography eluting withEtOAc/hexanes (85:15) followed by methylene chloride/methanol (9:1) toafford 2.9 g of impure 50a (R″=c-C₅H₁₁) as a thick gold syrup: ms (ESI)(M+H)⁺=373.

Step 3:3-Cyclohexylmethyl-4-hydroxymethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one

To a solution of 24a (R=Bn; R′=OH; R″=c-C₅H₁₁; 2.0 g (5.37 mmol) in 20mL EtOH was added 200 mg 20% Pd(OH)₂ on carbon. The mixture was stirredunder balloon pressure of H₂ at ambient temperature for 3.5 d. Thereaction was filtered through CELITE® and the filter cake washed withEtOH. The solvent was evaporated in vacuo and residue dried to give 1.52g (100%) of 50c (R″=c-C₅H₁₁) as a yellow syrup: ms (ESI) (M+H)⁺=283.

Step 4:3-cyclohexylmethyl-4-hydroxymethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester

To a solution of 50c (R″=c-C₅H₁₁; 1.52 g; 5.37 mmol) in 20 mL MeOH and10 mL 1M NaOH was added (Boc)₂O (1.17 g; 5.37 mmol) and the reaction wasstirred at ambient temperature for 21 h. The reaction was reduced involume and diluted with water and EtOAc. The aqueous phase was extractedaqueous two times with EtOAc. The combined organic phases were washedsequentially with water and brine, dried over sodium sulfate andconcentrated in vacuo to afford a yellow oil. The crude product waspurified by flash chromatography on silica gel eluting with a gradientof EtOAc/hexane (1:1→7:3) to give 650 mg (32%) of 50b (R″=c-C₅H₁₁) as aclear glass: ms (ESI) (M+H)⁺=383.

Step 5:3-Cyclohexylmethyl-4-ethoxymethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester

To a suspension of NaH (25 mg; 0.62 mmol; 60% NaH in mineral oil) in 5mL THF was added a solution of 50b (R″=c-C₅H₁₁; 217 mg; 0.57 mmol) and10 mL THF. After 15 minutes, ethyl iodide (97 mg; 0.62 mmol) was addedand the reaction was stirred at ambient temperature for 2.5 d. Thereaction was quenched with water and diluted with ethyl acetate. Thephases were separated and the aqueous phase extracted two times withEtOAc. The combined organic phases were washed sequentially with waterand brine, dried over sodium sulfate and concentrated in vacuo to afforda yellow oil. The crude product was purified by flash chromatography onsilica gel eluting with EtOAc/hexane (1:1) to give 157 mg (67%) of 51c(R″=c-C₅H₁₁) as a clear glass: ms (ESI) (M+H)⁺=411.

Step 6:3-cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-ethoxymethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one

3-Cyclohexylmethyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-4-ethoxymethyl-1-oxa-3,8-diaza-spiro[4.5]decan-2-one(I-11) was obtained from 51c c-C₅H₁₁) utilizing the procedures in step 3of example 2 and step 5 of example 1. The crude product was purified byflash chromatography on silica gel eluting with a gradient of methylenechloride/MeOH (90:1→90:4) to afford 189 mg (95% theory) of I-11 as aclear oil: ms (ESI) (M+H)⁺=526.

EXAMPLE 75-butyl-3-cyclohexylmethyl-9-(2,6-dimethyl-benzoyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one (I-76)

Step 1: 2-(1-Benzyl-4-hydroxy-piperidin-4-yl)-hexanenitrile

To a solution of 10 g, 12.4 mmol of hexanenitrile in 100 mL of THF at−78° C. was added of n-BuLi (41.2 mL, 103 mmol of 2.5M in hexane)dropwise over 10 m. After 4 h the reaction was poured onto a mixture ofsaturated NH₄Cl, extracted with EtOAc, the combined EtOAc extracts werewashed with brine and the organic layer dried over sodium sulfate. Afterfiltration the solvents were removed in vacuo and the crude residue waspurified by flash chromatography on silica gel utilizing a gradientelution of (10-50% EtOAc/hexane) to afford 15.7 g of 27 (R′=n-Bu) asorange oil (53% theory).

Step 2: 9-benzyl-5-butyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one

To an ice-cold solution of 10 g, 34.9 mmol 27 (R′=n-Bu) in 100 mL THFwas added lithium aluminum hydride (52.4 mL; 52.4 mmol; 1.0 M LAH inTHF). After 1 h the reaction was quenched by the addition of 2 mL water,2 mL 2N NaOH and 6 mL water with stirring. The reaction was stirred for30 m then filtered and the filtrate washed with EtOAc. The combinedorganic phases were washed with brine, dried over sodium sulfate andevaporated to dryness. The crude product was taken up in 60 mL of THFand carbonyldiimidazole (17 g, 104.7 mmol) was added. After stirring atfor 48 h, the reaction mixture was poured onto brine, the organic layerseparated, dried over sodium sulfate and concentrated to dryness. Theresidue was purified by flash chromatography on silica gel eluting witha gradient (50% EtOAc/hexane to 1% MeOH/EtOAc) to afford 2.3 g of pure29 (R′=Bu) along with 9 g. of partially purified product.

Step 39-Benzyl-5-butyl-3-cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one

To a solution of 27 (R′=n-Bu; 1.8 g, 19 mmol) in 30 mL of NMP was addedNaH (0.27 g, 6.8 mmol). The reaction was stirred at RT. After 30minutes, cyclohexylmethyl bromide was added (1.2 mL, 8.5 mmol). Thereaction mixture was heated to 80° C. for 16 h, cooled to RT and thereaction mixture was poured onto brine. The organic layer separated,dried over sodium sulfate and concentrated to dryness. The residue waspurified by flash chromatography on silica eluting with a gradient(10-50% acetone/hexane) to afford 30 (R′=n-Bu; R″=c-C₅H₁₁; 1.5 g; 65%theory).

Step 4:5-Butyl-3-cyclohexylmethyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one

A mixture of 30 (R′=n-Bu; R″=c-C₅H₁₁; 1.5 g, 3.6 mmol), 0.24 g Pd(OH)₂and 2 ammonium formate (3 g, 36.4 mmol) in 30 mL EtOH was heated atreflux. After 3 h, 10 mL 10% aqueous ammonium hydroxide was added andmixture was reheated to reflux. After 1 h, the reaction mixture wascooled to RT, filtered through CELITE®, washed with EtOH, concentratedto dryness and the residue purified by silica gel flash chromatographyeluting with a gradient (EtOAc to 20% MeOH/EtOAc containing 0.4% NH₄OH)to afford 30 (R′=n-Bu; R″=c-C₅H₁₁; 0.92 g, 79% theory) as a clear oil.

The final product 1-76 was prepared by treating piperidine 30 (R′=n-Bu;R″=c-C₅H₁₁) as described in step 5 of Example 1.

EXAMPLE 8

Step 1 (4-fluoro-phenyl)carbamic acid, tert-butyl ester

To a solution of 25 mL p-fluoroaniline (264 mmol) in 400 mL anhydrousTHF was added 59.3 g di-tert-butyl dicarbonate (272 mmol) in threeportions. The reaction mixture was maintained under a nitrogenatmosphere and heated at reflux for 3 hours. The mixture was cooled toroom temperature and the solvent was evaporated under reduced pressure.The residue was dissolved in 300 mL of EtOAc. The organic phase waswashed sequentially with 2N HCl and brine, dried over sodium sulfate andthe solvent was evaporated in vacuo. The solid was recrystallized fromboiling hexanes to provide 47.4 g (85% theory) of(4-fluoro-phenyl)carbamic acid tert-butyl ester (10): ms M⁺=212.

Step 2:spiro[6-fluoro-4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one-carbamicacid tert-butyl ester

To a solution of (4-fluoro-phenyl)carbamic acid tert-butyl ester (16.0g; 75.8 mmol) in 300 mL anhydrous THF at −78° C. was added dropwisetert-butyl lithium at a rate sufficient to maintain the internaltemperature below −75° C. The reaction mixture stirred at −78° C. for anadditional 30 m. The reaction mixture was warmed to −25° C. and stirredfor two h. The reaction mixture was cooled back to −78° C. and asolution of 15.1 g of 4-oxo-piperidine-1-carboxylic acid ester (75.8mmol) in 160 mL anhydrous THF was added dropwise. The reaction mixturestirred at −78° C. for four h. A solution of 1 mL potassiumtert-butoxide (1.0 M in tetrahydrofuran) was added. The reaction mixturewas allowed to warm to RT slowly over an 18 h period. The crude mixturewas diluted with 300 mL Et₂O and the organic phase washed sequentiallywith 2N HCl, water and brine. The organic phase was dried over sodiumsulfate and concentrated under in vacuo. The residue was triturated withEtOAc to provide 10.61 g (42%) ofspiro[4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one-BOC (33) as a solid:ms M⁺=337.

Step 3:4-cyclohexylmethyl-spiro[6-fluoro-4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one-carbamicacid tert-butyl ester

To a solution of 2.0 g of 33 (5.9 mmol) in 40 mL DMF was added 492 mgsodium hydride (10.7 mmol, 60% dispersion in mineral oil). The reactionmixture stirred for one h and 1.86 mL cyclohexylmethyl bromide (13.3mmol) was added dropwise. The reaction mixture was heated to 70° C. for18 h, then cooled to room temperature and diluted with 200 mL of water.The mixture was extracted thrice with EtOAc. The organics were combined,dried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel (10%EtOAc/hexanes) to afford 1.21 g (47%) of 34 (R″=c-C₅H₁₁): ms M⁺=433.

Step 4:3-cyclohexylmethyl-spiro[4H-3,1-6-fluorobenzoxazine-4,4′-piperidin]-2(1H)-one

To a solution of 1.2 g of 34 (R″=c-C₅H₁; 2.8 mmol) in 10 mLdichloromethane was added 10 mL TFA. The reaction mixture stirred undera nitrogen atmosphere for 18 hours. The solvent was removed underreduced pressure to afford the trifluoroacetic acid salt of 35(R″=c-C₅H₁₁). The trifluoroacetate salt was dissolved in 20 mLdichloromethane and 20 mL of aqueous saturated sodium bicarbonate wasadded. The reaction mixture stirred for 20 m after which 40 mL ofdichloromethane was added. The organic layer was separated and theaqueous layer was extracted with dichloromethane. The combined organiclayers were dried over sodium sulfate and concentrated under in vacuo toafford 918 mg (99%) of 35 (R″=c-C₅H₁₁): ms M⁺=333.

Reductive amination with N-(2,6-dimethylbenzoyl)-4-piperidone to affordI-423 was carried out as described in step 5 of Example 1

EXAMPLE 94-Butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(2-methoxy-ethyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;compound with trifluoro-acetic acid (I-81)

Step 1: 4-Butyl-1-oxa-3,8-diazaspiro[4.5]decane-2-one

2.0 g (5.8 mmol) of4-butyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid benzylester 12 (R=CBZ; R′=n-Bu) was dissolved in 25 mL of EtOH and Pd/C (10mol %; 10% by weight, dry basis, Degussa type) was added. The reactionmixture stirred under a hydrogen atmosphere for 18 h. The solution wasfiltered through a pad of CELITE® and washed twice with EtOH.Evaporation of the combined filtrate and washes under reduced pressureyielded 1.09 g (88%) of 4-butyl-1-oxa-3,8-diaza-spiro[4.5]decane-2-one12 (R=H; R′=n-Bu): ms [M]⁺=213.

Step 2:4-butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidinyl-4-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one

To a solution of 4-butyl-1-oxa-3,8-diaza-spiro[4.5]decane-2-one (12:R=H; R′=n-Bu; 1.09 g; 5.1 mmol)) in 30 mL DCM was added 1.24 g (5.4mmol) of 1-(2,6-dimethyl-benzoyl)-piperidin-4-one followed by 2.1 mL(7.1 mmol) of Ti(IV)(O-i-Pr)₄ The reaction mixture stirred undernitrogen for 18 h. of Sodium triacetoxyborohydride (1.6 g: 7.7 mmol) wasadded to the reaction mixture followed by glacial HOAc (0.365 mL; 6.4mmol). The reaction mixture stirred for 24 h. Aqueous ammonia (20 mL;10% aqueous solution) was added and the solution stirred for anadditional 10 min. The mixture was filtered by gravity through acartridge of ChemElute™. The organics were evaporated under reducedpressure and the residue was purified by flash chromatography on silicagel with gradient elution (2% to 10% methanol in ethyl acetate with 0.4%ammonia) to provide 1.6 g (73%) of4-butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decane-2-one:ms [M]⁺=428.

Step 3:5-butyl-3-(2-methoxyethyl)-9-[2-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.4]decan-2-one

To a solution of 21 mg (0.05 mmole) of4-butyl-8-[1-(2,6-dimethyl-1-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diazaspiro[4.5]decane-2-onedissolved in 1 mL of dry 1,4-dioxanes in a screw-capped test tube wasadded 100 mg of 10% KF on alumina and 7.1 uL (0.075 mmole) of2-bromoethylmethyl ether. The tube was sealed and heated at 110° C. for18 h. The reaction was filter through CELITE® and the filter bed waswashed methylene chloride (3×0.5 mL). The combine filtrate and washeswere concentrated under reduced pressure. The residue was purified usingreverse-phase semi-preparatory HPLC on Aquisil with gradient elution(10%-90% acetonitrile/0.1% aqueous TFA buffer) which afforded 16 mg(52%) of I-81 as the trifluoroacetate salt.

EXAMPLE 10

Step 1

To a solution of 600 mg (1.73 mmol) of 12 (R=Z; R′=n-Bu) in 10 mL THF at−78° C. was added n-BuLi (0.70 mL; 1.90 mmol; 2.5M in hexanes). Thereaction mixture was stirred at −78° C. for 30 min followed by dropwiseaddition of (1S)(−)-camphanic acid chloride (412 mg; 1.90 mmol)dissolved in 3 ml THF. The reaction mixture was stirred at −78° C. for15 min, then ambient temperature for 4 h. The reaction was quenched withsaturated ammonium chloride and diluted with EtOAc and water. The phaseswere separated and the aqueous extracted three times with EtOAc. Thecombined organic extracts were washed sequentially with saturatedNaHCO₃, water and brine, dried over sodium sulfate and evaporated to agold oil. The diastereomers (38a and 38b) were separated by flashchromatography eluting with a gradient of hexane/EtOAc (8:2 to 7:3) toafford 150 mg (16%) of the more nonpolar isomer was isolated as acolorless thick oil: ms (ESI) [M+H]⁺=527. A second fraction of 210 mg(23%) of the less nonpolar isomer was isolated as a white crystallinesolid: ms (ESI) [M+H]⁺=527.

Step 2

To a solution of 210 mg (0.40 mmol) of 38a or 38b from step 1 in 6 mLTHF and 2 mL water at 0° C. was added LiOH monohydrate (36 mg; 0.86mmol). After stirring at 0° C. for 2 h, the THF was stripped and theresidue was diluted with saturated NaHCO₃ and ether. The phases wereseparated and the aqueous extracted two times with ether. The combinedextracts were washed with brine, dried over sodium sulfate andevaporated to an off-white powder which was dried in vacuo to afford 135mg (97%) of the carbamate 39: ms (ESI) [M+H]⁺=347.

The resolved oxazolinones 39a and 39b are converted to (R)- and (S)-I-1as described in Example 1.

EXAMPLE 11 Chiral synthesis of (S)5-butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethylbenzoyl)-piperidin-4-yl]-1-oxa-3,9-diazospiro[5.5]undecan-2-one(SCHEME 8)

To a solution of 85.18 g (206.0 mmol) of pentyltriphenylphosphinebromide in THF (330 mL) cooled to −78° C. was added n-butyl lithium(80.8 mL, 201.9 mmol, 2.5M butyl lithium in hexanes). After 30 min, asolution of 1-BOC-4-piperidone (38.99 g, 195.7 mmol) in THF (175 mL) wasadded dropwise over 30 min. The cooling bath was removed and thereaction mixture was stirred at RT. After 17 h, the reaction wasquenched with saturated NH₄Cl and diluted with EtOAc. Water was addeduntil two clear phases were obtained. The aqueous phase was extractedtwice with EtOAc. The combined extracts were washed sequentially withwater and brine, dried (Na₂SO₄), filtered and concentrated in vacuo toafford a gold oil. The crude product was purified by SiO₂ chromatographyeluting with Hex/EtOAc (85:15) to afford 18.1 g (36%) of4-pentylidene-piperidene-1-carboxylic acid tert-butyl ester (55) as acolorless oil: MS (ESI): m/z 254 (M+H).

Step 1—

A suspension of AD-Mix-β (100.0 g, 71.43 mmol), methanesulfonamide (6.80g, 71.43 mmol), tert-BuOH (270 mL) and water (360 mL) was stirred untila single clear phase was obtained. A solution of 55 (18.1 g, 71.43 mmol)and tert-BuOH (100 mL) was added. The resulting solution was stirred atRT for 3.5 h, cooled to 0° C. and Na₂SO₃ (107 g) was added. The reactionwas stirred vigorously for 1.5 h and diluted with water and EtOAc. Thephases were separated and the aqueous phase extracted aqueous two timeswith EtOAc. The combined organic phases were washed with brine, driedover (Na₂SO₄) and concentrated in vacuo. The crude product was purifiedby SiO₂ chromatography eluting with a gradient of hexane/EtOAc (1:0 to1:1) which afforded 18.7 g (91%) of 56: MS (ESI): m/z 288 (M+H).

Step 2—

To a solution of 56 (17.2 g, 59.85 mmol) and EtOAc/DCM (860 mL, 4:1) at0° C. was added methanesulfonyl chloride (9.3 mL, 119.7 mmol) and TEA(18.4 mL, 131.7 mmol). The cooling bath was removed and the mixture wasstirred at RT for 45 min. The reaction was quenched by addition of waterand diluted with EtOAc. The aqueous phase was extracted twice with EtOAcand the combined EtOAc extracts were washed sequentially with 1M HCl,water, saturated NaHCO₃, water and brine. The EtOAc solution was dried(Na₂SO₄) and concentrated in vacuo. A 2 L 3 neck flask was charged withNaH (3.59 g, 89.78 mmol, 60% NaH in mineral oil). The flask was cooledin an ice bath and MeOH (400 mL) was slowly added. The solution wasstirred at 0° C. for 10 min and then a solution of the mesylate and MeOH(200 mL) were added. The reaction was stirred at 0° C. for 1.5 h,concentrated in vacuo and the residue was partitioned between water andEtOAc. The aqueous phase was extracted aqueous twice with EtOAc and thecombined extracts we rewashed with brine, dried (Na₂SO₄) andconcentrated in vacuo to a yellow oil. The crude material was purifiedby SiO₂ chromatography eluting with a hexane/EtOAc gradient (9:1 to 8:2)to afford 14.3 g (89%) of 57 as a colorless oil: MS (ESI): nm/z 270(M+H), 98% ee by chiral GC (CyclosilB, 30 m×0.25 mm; 150° C. isothermal;R_(t)=57.1 min).

Step 3—

To a solution of 57 (16.2 g, 59.85 mmol) and THF (450 mL) cooled to 0°C. was added dropwise Et₃AlCN (239 mL, 239 mmol, 1M in toluene). Thecooling bath was removed and the mixture was stirred at RT for 16 h. Thereaction was cooled to 0° C., quenched with 1 M NaOH and diluted withEtOAc. The aqueous phase was extracted twice with EtOAc. The combinedextracts were washed with brine, dried (Na₂SO₄), filtered and thesolvents concentrated in vacuo. The crude product was purified by SiO₂chromatography eluting with a hexane/EtOAc (1:0 to 8:2) to afford 10.3 g(58%) of 58a as a viscous oil: MS (ESI) m/z 297 (M+H).

Step 4—

To a solution of 58a (10.30 g, 34.75 mmol) and MeOH (400 mL) was addedCoCl₆.6H₂O (16.54 g, 69.50 mmol) followed by NaBH₄ (13.15 g, 347.50mmol) in 2 g portions over 2 h. The black reaction mixture was stirredat RT for 3 days. The reaction was slowly acidified to pH 4 with 1M HCl,filtered through CELITE® and the filter cake washed with water. The pinkfiltrate was extracted with Et₂O and made basic conc. NH₄OH. The aqueoussolution was extracted three times with EtOAc. The combined organic waswashed with brine, dried (Na₂SO₄) and concentrated to a light yellow oilin vacuo. The oil was dried to afford 9.0 g (86%) of 58b which was usedwithout further purification: MS (ESI) m/z 301 (M+H).

Step 5—

To a solution of 58b (9.0 g, 29.9 mmol) in THF (250 mL) was added1,1′carbonyldiimidazole (9.7 g, 59.9 mmol) and the reaction was stirredat RT for 17 h. The solvent was concentrated in vacuo and the residuepartitioned between 0.5 M HCl and EtOAc. The aqueous phase was extractedtwo times with EtOAc and combined extracts washed sequentially with 0.5MHCl, saturated NaHCO₃, water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude material was purified by SiO₂chromatography eluting with a DCM/MeOH gradient (1:0 to 99:1) to afford6.75 g (69%) of 59a as a white foam: MS (ESI) m/z 327 (M+H),[α_(D)]²⁵=+31.2° (MeOH).

Step 6—

Introduction of the N-cyclohexylmethyl substituent into 59a wasaccomplished as described in step 3 of Example 1 which afforded 59b.

Step 7—

Deprotection of 59b followed the procedure described in step 3 ofExample 8. Purification by SiO₂ chromatography eluting with aCH₂Cl₂/MeOH (1:0 to 99:1) gradient afforded the deprotected piperidinein 91% yield as a white solid: MS (ESI), m/z 423 (M+H), [α_(D)]²⁵=+38.1°(MeOH).

Step 8—

The title compound was obtained from the product from step 7 and 15 bythe procedure described in step 5 of Example 1. 71% from the titlecompound of step G following the procedure described in preparation XX.Purification by SiO₂ chromatography eluting with a CH₂Cl₂/MeOH (1:0 to9:1) gradient afforded I-421 as a white solid: MS (ESI): m/z 538 (M+H),[α_(D)]²⁵=+24.4° (MeOH), mp=78.8-80.3° C.

EXAMPLE 12 Human CCR5 Receptor-Ligand Binding Assay Protocol

Human CCR5 receptor (Genebank ID: 29169292) was cloned into mammalianexpression vector, pTarget (Promega). The construct was transfected intoCHO-G_(α16) cells by using Fugene Reagent (Roche). Clones were selectedunder antibiotic pressure (G418 and Hygromycin) and sorted 4 times witha fluorescence activates cell sorter and a monoclonal antibody specificfor CCR5 receptor (BD Biosciences Pharmigen, Mab 2D7, Cat. No. 555993).The clone with highest expression (100,000 copies per cell) was chosenfor the binding assays.

Adherent cells in 225 mL tissue culture flask (˜90% confluent) wereharvested using 1 mM EDTA in PBS (phosphate-buffered saline) withoutCa²⁺ and Mg²⁺. Cells were washed twice with PBS containing no Ca²⁺ andMg²⁺. CHO-G_(α16)-hCCR5 cells were then resuspended (1×10⁶/ml) in icecold binding buffer (50 mM HEPES, 1 mM CaCl₂, 5 mM MgCl₂, 0.5% BSA,0.05% NaN₃, pH 7.24), pH 7.4), supplemented with freshly made 0.5% BSAand 0.05% NaN₃.

Eighty μl CHO-G_(α16)-hCCR5 (1×10⁶/ml) cells were added to 96 wellplates. All dilutions were made in binding buffer (50 mM HEPES, 1 mMCaCl₂, 5 mM MgCl₂, 0.5% BSA, 0.05% NaN₃, pH 7.24).

The plates were incubated on a cell shaker at RT for 2 h with a finalconcentration of 0.1 nM ¹²⁵I RANTES or ¹²⁵I MIP-1α or ¹²⁵I MIP-1α. Thecompound dilutions were made in PBS, 1% BSA. Total reaction volume was100 μl per well. The test compounds were added to the cells prior to theaddition of radioligand.

After incubation, the cells were harvested onto GF/C filter plates usingPackard cell harvester. Filters were pretreated with 0.3% PEI/0.2% BSAfor 30 min. The filter plate was washed rapidly 5 times with 25 mMHEPES, 500 mM NaCl, 1 mM CaCl₂ and 5 mM MgCl₂ adjusted to pH 7.1. Plateswere dried in oven (70° C.) for 20 min, added with 40 μl scintillationfluid and sealed with Packard TopSeal-A. Packard Top Count was used tomeasure of the radioactivity for 1 min per well.

Total binding was determined with control wells added with radioisotopeand buffer and the non-specific binding was determined using an excesscold RANTES to some of the control wells. Specific binding wasdetermined by subtracting the non-specific form total binding. Resultsare expressed as the percentage of specific ¹²⁵I RANTES binding. IC₅₀values were determined using varying concentrations of the test ligandin triplicates and the data was analyzed using GraphPad Prism (GraphPad,San Diego, Calif.).

Binding Compound IC₅₀ (μM) No. RANTES Mip-1a Mip-1b I-1 0.014 0.0180.013 I-90 0.0051 — 0.0018 I-159 0.0051 0.0045 0.0105 I-212 0.0073 — —I-214 0.0082 — — I-415 0.0077 — <0.0015

EXAMPLE 13 Formulations

Pharmaceutical compositions of the subject Compounds for administrationvia several routes were prepared as described in this Example.

Composition for Oral Administration (A) Ingredient % wt./wt. Activeingredient 20.0% Lactose 79.5% Magnesium stearate  0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration (B) Ingredient % wt./wt. Activeingredient 20.0%  Magnesium stearate 0.5% Crosscarmellose sodium 2.0%Lactose 76.5%  PVP (polyvinylpyrrolidine) 1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration (C) Ingredient % wt./wt. Activecompound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben0.15 g Propyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70%solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 mlColorings 0.5 mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation (D) Ingredient % wt./wt. Active ingredient 0.25 gSodium Chloride qs to make isotonic Water for injection to 100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation (E) Ingredient % wt./wt. Active ingredient  1.0%Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Topical Formulation (F) Ingredients grams Active compound 0.2-2 Span 602 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propylparaben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Nasal Spray Formulations (G)

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 24 sprays every 4-12 hours.

The features disclosed in the foregoing description, or the followingclaims, expressed in their specific forms or in terms of a means forperforming the disclosed function, or a method or process for attainingthe disclosed result, as appropriate, may, separately, or in anycombination of such features, be utilized for realizing the invention indiverse forms thereof.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

1-20. (canceled)
 21. A compound according to formula Ia or Ib,

wherein: A is (CH₂)_(q); R¹ is C(═O)R⁴, C(═O)X, or S(O)_(p)R⁴; X isNR⁵R⁶ or OR¹¹; R^(2a) and R^(2b) are (A), independently (i) hydrogen,(ii) C₁₋₁₀ alkyl, (iii) C₂₋₁₀ alkenyl (iv) C₁₋₁₀ haloalkyl, (v) C₃₋₇cycloalkyl, (vi) C₃₋₇ cycloalkyl-C₁₋₃ alkyl, (vii) C₁₋₁₀ heteroalkyl,(viii) C₁₋₁₀ alkylidene, (ix) C₁₋₁₀ heteroalkylidene, (x) aryl, (xi)aryl-C₁₋₃ alkyl, (xii) heteroaryl, (xiii) heteroaryl-C₁₋₃ alkyl, (xiv)C₁₋₁₀ alkyl wherein 2 or 3 nonadjacent carbon atoms are independentlyreplaced with —O—, —S(O)_(p)—, —NH— or NR⁵, (xv) —(CH₂)_(w)R⁸ wherein wis an integer form 2 to 6, and the C₂-C₆ alkylene chain optionallycontains a double bond; (xvi) —(CH₂)_(w)CH═NR⁹ wherein w is an integerfrom 2 to 6; or (B), together with the carbon atoms to which they areattached, are o-phenylene optionally substituted with 1 to 3substituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ thioalkyl, C₁₋₆ alkylsulfonyl,hydroxyl, halogen, NR^(5a)R^(6a), cyano and nitro with the proviso thatif R^(2a), R^(2b), together with the carbon atoms to which they areoptionally substituted o-phenylene, m is 1; R³ is (i) C₁₋₁₀ alkyl, (ii)C₂₋₁₀ alkenyl (iii) C₁₋₁₀ heteroalkyl, (iv) C₃₋₇ cycloalkyl, (v) C₁₋₆alkyl-C₃₋₇ cycloalkyl, (vi) heterocycle C₁₋₆ alkyl, (vii) aryl, (viii)aryl-C₁₋₃ alkyl, (ix) heteroaryl, (x) heteroaryl C₁₋₆ alkyl, (xi)C(═O)R^(3a) wherein R^(3a) is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₃₋₇cycloalkyl, or (xii) a fragment of formula IIa-IIc;

R⁴ is (i) C₁₋₁₀ alkyl, (ii) C₃₋₇ cycloalkyl-C₁₋₁₀ substituted alkyl,(iii) heterocycle, (iv) aryl, or (v) heteroaryl; R⁵ and R⁶ are (A) whentaken independently are hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₃₋₇cycloalkyl, C₁₋₆ alkyl-C₃₋₇ cycloalkyl, heterocycle C₁₋₆ alkyl, aryl,aryl-C₁₋₃ alkyl, heteroaryl or heteroaryl C₁₋₆ alkyl; or, (B) C₃₋₆alkylene or [(CH₂)₂]₂O thereby forming a morpholine ring when takentogether; R^(5a) and R^(6a) are (A) hydrogen, C₁₋₆ alkyl or C₁₋₆alkylcarbonyl when taken independently or (B) C₃₋₆ alkylene or[(CH₂)₂]₂O when taken together; R⁷ is hydrogen, cyano or C₁₋₆ alkyl; R⁸is —CN, —NO₂, CONR^(5a)R^(6a), COR⁹, —NHSO₂C₁₋₆alkyl; R⁹ is OH or C₁₋₆alkoxy; R¹⁰ is N or N⁺—O⁻; R¹¹ is C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₃₋₇cycloalkyl, C₁₋₆ alkyl-C₃₋₇ cycloalkyl, heterocycle C₁₋₆ alkyl, aryl,aryl-C₁₋₃ alkyl, heteroaryl or heteroaryl C₁₋₆ alkyl; m is 0; n isindependently 0 to 2; o is independently 0 or 1; p is 0 to 2; q is 1 to3; wherein, each said heteroaryl is independently selected from thegroup consisting of pyridyl, 1-oxy-pyridinyl, pyrimidyl, oxypyrimdinyl,pyrazinyl, pyridazinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl indolinyl,N-Boc-indolinyl, quinolinyl, isoquinolinyl, benzofuranyl,4,5,6,7-tetrahydrobenzofuranyl and 1,2,3,4-tetrahydroacridinyl; eachsaid aryl and said heteroaryl are optionally independently substitutedwith 1 to 3 substituents selected from the group consisting of hydroxy,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆thioalkyl, aryl, aryl C₁₋₃ alkyl, aryloxy, heteroaryloxy, thioaryl,thioheteroaryl, aryl C₁₋₃ alkoxy, heteroaryl, heterocyclyl, heterocycleC₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, —NHSO₂C₁₋₆ alkyl, SO₂NR^(5a)R^(6a),(CH₂)_(u)CO₂R⁹, (CH₂)_(u)CONR^(5a)R^(6a), —X¹C(═O)X², C₁₋₁₀alkylcarbonyl, halogen, NR^(5a)R^(6a), cyano, nitro and C₁₋₁₀ alkylwherein 2 or 3 nonadjacent carbon atoms are independently replaced with—O—, —S(O)_(p)—, —NH— or NR⁵, wherein u is an integer from 0 to 6, X¹ isNR^(5b) or O; X² is NR⁵R⁶ or OR³ and R^(5b) is H or C₁₋₆ alkyl; eachsaid heterocycle is independently selected from the group consisting ofpyrrolidinyl, 1-methyl-pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, tetrahydrofuranyl, dioxolanyl and pyranyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of hydroxy C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,C₁₋₆ thioalkyl, C₁₋₆ alkylsulfonyl, halogen, NR^(5a)R^(6a), cyano andnitro; pure enantiomers, partially resolved enantiomers, racemicmixtures and pharmaceutically acceptable acid addition salts thereof.22. A compound according to claim 1 with formula Ic,

R^(2a) is C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₃ alkyl, C₁₋₁₀ heteroalkyl, C₁₋₁₀ alkylidene, C₁₋₁₀heteroalkylidene or C₁₋₁₀ alkyl wherein 2 or 3 nonadjacent carbon atomsare independently replaced with —O—, —S(O)_(p)—, —NH— or —NR⁵—; R^(2b)is hydrogen; R³ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyl-C₃₋₇cycloalkyl, optionally substituted aryl, optionally substitutedaryl-C₁₋₃ alkyl, optionally substituted heteroaryl, optionallysubstituted heteroaryl-C₁₋₃ alkyl; R⁴ is C₁₋₁₀ alkyl, optionallysubstituted aryl or optionally substituted heteroaryl; R⁷ is hydrogen,or C₁₋₆ alkyl; n and o are 1; and, p is
 2. 23. A compound according toclaim 3 wherein R⁷ is hydrogen or methyl.
 24. A compound according toclaim 4 wherein R′ is COR⁴; R^(2a) is C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl orC₁₋₁₀ alkyl wherein 2 or 3 nonadjacent carbon atoms in the alkyl chainoptionally can be independently replaced with —O—, —S(O)_(p)—, —NH— orNR⁵; R⁴ is optionally substituted aryl or optionally substitutedheteroaryl; and,
 25. A compound according to claim 5 wherein R⁴ isoptionally substituted aryl.
 26. A compound according to claim 5 whereinR⁴ is optionally substituted heteroaryl.
 27. A compound according toclaim 8 wherein R⁴ is optionally substituted pyridyl, optionallysubstituted pyrimidinyl, optionally substituted pyrazolyl, optionallysubstituted oxazolyl, optionally substituted isoxazolyl or optionallysubstituted pyrrolyl.
 28. A compound according to claim 1 with theformula Id wherein

R²′ is C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₃ alkyl, C₁₋₁₀ heteroalkyl, C₁₋₁₀ alkylidene, C₁₋₁₀heteroalkylidene or C₁₋₁₀ alkyl wherein 2 or 3 nonadjacent carbon atomsare independently replaced with —O—, —S(O)_(p)—, —NH— or NR⁵; R^(2b) ishydrogen; R⁴ is optionally substituted aryl or optionally substitutedheteroaryl; R⁷ is hydrogen or C₁₋₆ alkyl; n and o are 1; and, p is 2.29. A compound according to claim 10 with the formula Id wherein A is(CH₂)₂.
 30. A pharmaceutical composition for the comprising a compoundaccording to either claim 21 admixed with at least one pharmaceuticalacceptable carrier, diluent or excipient.